Rich66
12-26-2009, 01:34 PM
Recent Results Cancer Res. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Recent%20Re sults%20Cancer%20Res.%27%29;) 2010;180:15-34.
HIF-1alpha and Cancer Therapy.
Koh MY (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Koh%20MY%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Spivak-Kroizman TR (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Spivak-Kroizman%20TR%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Powis G (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Powis%20G%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Most solid tumors develop regions of hypoxia as they grow and outstrip their blood supply. In order to survive in the stressful hypoxic environment, tumor cells have developed a coordinated set of responses orchestrating their adaptation to hypoxia. The outcomes of the cellular responses to hypoxia are aggressive disease, resistance to therapy, and decreased patient survival. A critical mediator of the hypoxic response is the transcription factor hypoxia-inducible factor 1 (HIF-1) that upregulates expression of proteins that promote angiogenesis, anaerobic metabolism, and many other survival pathways. Regulation of HIF-1alpha, a component of the HIF-1 heterodimer, occurs at multiple levels including translation, degradation, and transcriptional activation, and serves as a testimony to the central role of HIF-1. Studies demonstrating the importance of HIF-1alpha expression for tumor survival have made HIF-1alpha an attractive target for cancer therapy. The growing l.ist of pharmacological inhibitors of HIF-1 and their varied targets mirrors the complex molecular mechanisms controlling HIF-1. In this chapter, we summarize recent findings regarding the regulation of HIF-1alpha and the progress made in identifying new therapeutic agents that inhibit HIF-1alpha.
PMID: 20033376 [PubMed - as supplied by publisher]
Proc Natl Acad Sci U S A. (http://javascript%3cb%3e%3c/b%3E:AL_get%28this,%20%27jour%27,%20%27Proc%20Natl %20Acad%20Sci%20U%20S%20A.%27%29;) 2009 Dec 15;106(50):21306-11. Epub 2009 Dec 2.
Human cancers converge at the HIF-2{alpha} oncogenic axis.
Franovic A (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Franovic%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Holterman CE (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Holterman%20CE%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Payette J (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Payette%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Lee S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Lee%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
Cancer development is a multistep process, driven by a series of genetic and environmental alterations, that endows cells with a set of hallmark traits required for tumorigenesis. It is broadly accepted that growth signal autonomy, the first hallmark of malignancies, can be acquired through multiple genetic mutations that activate an array of complex, cancer-specific growth circuits [Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57-70; Vogelstein B, Kinzler KW (2004) Cancer genes and the pathways they control. Nat Med 10:789-799]. The superfluous nature of these pathways is thought to severely limit therapeutic approaches targeting tumor proliferation, and it has been suggested that this strategy be abandoned in favor of inhibiting more systemic hallmarks, including angiogenesis (Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: Mechanisms of anti-tumor activity. Nat Rev Cancer 8:579-591; Stommel JM, et al. (2007) Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318:287-290; Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727-739; Kaiser J (2008) Cancer genetics: A detailed genetic portrait of the deadliest human cancers. Science 321:1280-1281]. Here, we report the unexpected observation that genetically diverse cancers converge at a common and obligatory growth axis instigated by HIF-2alpha, an element of the oxygen-sensing machinery. Inhibition of HIF-2alpha prevents the in vivo growth and tumorigenesis of highly aggressive glioblastoma, colorectal, and non-small-cell lung carcinomas and the in vitro autonomous proliferation of several others, regardless of their mutational status and tissue of origin. The concomitant deactivation of select receptor tyrosine kinases, including the EGFR and IGF1R, as well as downstream ERK/Akt signaling, suggests that HIF-2alpha exerts its proliferative effects by endorsing these major pathways. Consistently, silencing these receptors phenocopies the loss of HIF-2alpha oncogenic activity, abrogating the serum-independent growth of human cancer cells in culture. Based on these data, we propose an alternative to the predominant view that cancers exploit independent autonomous growth pathways and reveal HIF-2alpha as a potentially universal culprit in promoting the persistent proliferation of neoplastic cells.
PMID: 19955413 [PubMed - in process]
Breast Cancer Res. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Breast%20Ca ncer%20Res.%27%29;) 2009;11(6):R84. Epub 2009 Nov 17.
Hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression in circulating tumor cells of breast cancer patients.
Kallergi G (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Kallergi%20G%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Markomanolaki H (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Markomanolaki%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Giannoukaraki V (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Giannoukaraki%20V%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Papadaki MA (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Papadaki%20MA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Strati A (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Strati%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Lianidou ES (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Lianidou%20ES%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Georgoulias V (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Georgoulias%20V%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Mavroudis D (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Mavroudis%20D%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Agelaki S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Agelaki%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Voutes, Heraklion, 71110, Greece. kalergi@med.uoc.gr
Abstract
Introduction
The detection of peripheral blood circulating tumor cells (CTCs) and bone marrow disseminated tumor cells (DTCs) in breast cancer patients is associated with a high incidence of disease relapse and disease-related death. Since hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) play an important role in angiogenesis and tumor progression, the purpose of the current study was to investigate their expression in CTCs.
Methods
The expression of cytokeratins (CK), VEGF, vascular endothelial growth factor receptor-2 (VEGFR2), HIF-1α and phosphorylated-focal adhesion kinase (pFAK) in CTCs from 34 patients with metastatic breast cancer who had detectable CK-19 mRNA-positive CTCs was assessed using double staining experiments and confocal laser scanning microscopy. Peripheral blood mononuclear cells (PBMCs) were stained with a monoclonal A45-B/B3 pancytokeratin antibody in combination with either VEGF or VEGFR2 or HIF-1α or pFAK antibodies, respectively.
Results
pFAK expression in CTCs was detected in 92% of patients whereas expression of VEGF, VEGFR2 and HIF-1α was observed in 62%, 47% and 76% of patients, respectively. VEGF, VEGFR2, HIF-1α and pFAK were expressed in 73%, 71%, 56% and 81%, respectively, of all the detected CTCs. VEGF mRNA was also detected by quantitative real-time RT-PCR in immunomagnetically-separated CTCs. Double and 3 triple staining experiments in cytospins of immunomagnetically-isolated CTCs showed that VEGF co-expressed with HIF-1α and VEGFR2.
Conclusions
The expression of pFAK, HIF-1α, VEGF and VEGFR2 in CTCs of patients with metastatic breast cancer could explain the metastatic potential of these cells and may provide a therapeutic target for their elimination.
PMID: 19919679 [PubMed - in process]
British Journal of Cancer (2010) 102, 789–795. doi:10.1038/sj.bjc.6605551 www.bjcancer.com (http://www.bjcancer.com/)
Published online 26 January 2010
Hypoxia inducible factors in cancer stem cells
J M Heddleston<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605551a.html#aff1)</sup>, Z Li<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605551a.html#aff1)</sup>, J D Lathia<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605551a.html#aff1)</sup>, S Bao<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605551a.html#aff1)</sup>, A B Hjelmeland<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605551a.html#aff1)</sup> and J N Rich<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605551a.html#aff1)</sup>
<sup>1</sup>Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland 44195, OH, USA
Correspondence: Professor JN Rich, E-mail: richj@ccf.org
Received 14 October 2009; Revised 8 December 2009; Accepted 22 December 2009; Published online 26 January 2010.
Top of page (http://www.nature.com/bjc/journal/v102/n5/abs/6605551a.html#top) Abstract
Oxygen is an essential regulator of cellular metabolism, survival, and proliferation. Cellular responses to oxygen levels are monitored, in part, by the transcriptional activity of the hypoxia inducible factors (HIFs). Under hypoxia, HIFs regulate a variety of pro-angiogenic and pro-glycolysis pathways. In solid cancers, regions of hypoxia are commonly present throughout the tissue because of the chaotic vascular architecture and regions of necrosis. In these regions, the hypoxic state fluctuates in a spatial and temporal manner. Transient hypoxic cycling causes an increase in the activity of the HIF proteins above what is typical for non-pathologic tissue. The extent of hypoxia strongly correlates to poor patient survival, therapeutic resistance and an aggressive tumour phenotype, but the full contribution of hypoxia and the HIFs to tumour biology is an area of active investigation. Recent reports link resistance to conventional therapies and the metastatic potential to a stem-like tumour population, termed cancer stem cells (CSCs). We and others have shown that within brain tumours CSCs reside in two niches, a perivascular location and the surrounding necrotic tissue. Restricted oxygen conditions increase the CSC fraction and promote acquisition of a stem-like state. Cancer stem cells are critically dependant on the HIFs for survival, self-renewal, and tumour growth. These observations and those from normal stem cell biology provide a new mechanistic explanation for the contribution of hypoxia to malignancy. Further, the presence of hypoxia in tumours may present challenges for therapy because of the promotion of CSC phenotypes even upon successful killing of CSCs. The current experimental evidence suggests that CSCs are plastic cell states governed by microenvironmental conditions, such as hypoxia, that may be critical for the development of new therapies targeted to disrupt the microenvironment.
Cancer Res. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Cancer%20Re s.%27%29;) 2009 Sep 15;69(18):7160-4. Epub 2009 Sep 8.
mTOR signal and hypoxia-inducible factor-1 alpha regulate CD133 expression in cancer cells.
Matsumoto K (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Matsumoto%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Arao T (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Arao%20T%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Tanaka K (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Tanaka%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Kaneda H (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Kaneda%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Kudo K (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Kudo%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Fujita Y (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Fujita%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Tamura D (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Tamura%20D%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Aomatsu K (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Aomatsu%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Tamura T (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Tamura%20T%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Yamada Y (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Yamada%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Saijo N (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Saijo%20N%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Nishio K (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Nishio%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
The underlying mechanism regulating the expression of the cancer stem cell/tumor-initiating cell marker CD133/prominin-1 in cancer cells remains largely unclear, although knowledge of this mechanism would likely provide important biological information regarding cancer stem cells. Here, we found that the inhibition of mTOR signaling up-regulated CD133 expression at both the mRNA and protein levels in a CD133-overexpressing cancer cell line. This effect was canceled by a rapamycin-competitor, tacrolimus, and was not modified by conventional cytotoxic drugs. We hypothesized that hypoxia-inducible factor-1 alpha (HIF-1 alpha), a downstream molecule in the mTOR signaling pathway, might regulate CD133 expression; we therefore investigated the relation between CD133 and HIF-1 alpha. Hypoxic conditions up-regulated HIF-1 alpha expression and inversely down-regulated CD133 expression at both the mRNA and protein levels. Similarly, the HIF-1 alpha activator deferoxamine mesylate dose-dependently down-regulated CD133 expression, consistent with the effects of hypoxic conditions. Finally, the correlations between CD133 and the expressions of HIF-1 alpha and HIF-1 beta were examined using clinical gastric cancer samples. A strong inverse correlation (r = -0.68) was observed between CD133 and HIF-1 alpha, but not between CD133 and HIF-1 beta. In conclusion, these results indicate that HIF-1 alpha down-regulates CD133 expression and suggest that mTOR signaling is involved in the expression of CD133 in cancer cells. Our findings provide a novel insight into the regulatory mechanisms of CD133 expression via mTOR signaling and HIF-1 alpha in cancer cells and might lead to insights into the involvement of the mTOR signal and oxygen-sensitive intracellular pathways in the maintenance of stemness in cancer stem cells.
PMID: 19738050 [PubMed - indexed for MEDLINE]
Br J Cancer. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Br%20J%20Ca ncer.%27%29;). [Epub ahead of print]
Hypoxia potentiates Notch signaling in breast cancer leading to decreased E-cadherin expression and increased cell migration and invasion.
Chen J (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Chen%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Imanaka N (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Imanaka%20N%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Chen J (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Chen%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Griffin JD (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Griffin%20JD%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Background:Epithelial-to-mesenchymal transition (EMT) is associated with decreased adhesion and acquisition of metastatic potential of breast cancer cells. Epithelial-to-mesenchymal transition is mediated, in part, by two transcription repressors, Snail and Slug, that are known to be targets of the Notch signaling pathway, and JAGGED1-induced Notch activation increases EMT. However, the events that lead to increased Notch activity during EMT of breast cancer cells are unknown. Methods: The accumulation of hypoxia inducible factors (HIFs) under hypoxia was detected by western blot analysis, and their effects on Notch signaling were measured by an in vitro Notch reporter assay. The expression of Notch target genes under hypoxia was tested by real-time PCR. The knockdown of HIF-1alpha was mediated by retroviral delivery of shRNA. The expression of Slug and Snail under hypoxia was measured by real-time PCR. Breast cancer cell migration and invasion under hypoxia were tested with cell migration and invasion kits.Results:Hypoxia increased the expression of Notch target genes such as HES1 and HEY1 in breast cancer cells, as was expression of Notch receptors and ligands. The mechanism is likely to involve the accumulation of HIF-1alpha and HIF-2alpha in these cells by hypoxia, which synergised with the Notch co-activator MAML1 in potentiating Notch activity. Hypoxia inducible factor-1alpha was found to bind to HES1 promoter under hypoxia. Knockdown of HIF-1alpha with shRNA inhibited both HES1 and HEY1 expression under hypoxia. Hypoxia increased the expression of Slug and Snail, and decreased the expression of E-cadherin, hallmarks of EMT. Notch pathway inhibition abrogated the hypoxia-mediated increase in Slug and Snail expression, as well as decreased breast cancer cell migration and invasion. Conclusion:Hypoxia-mediated Notch signaling may have an important role in the initiation of EMT and subsequent potential for breast cancer metastasis. British Journal of Cancer advance online publication, 15 December 2009; doi:10.1038/sj.bjc.6605486 www.bjcancer.com (http://www.bjcancer.com).
PMID: 20010940 [PubMed - as supplied by publisher]
LINK (http://her2support.org/vbulletin/showthread.php?p=204345&highlight=hypoxia-inducible+factor#post204345) to cancer stem cell thread
Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1α/VEGF signaling pathways in human breast cancer cells (http://www.mdlinx.com/readArticle.cfm?art_id=2835257)
International Journal of Cancer, 08/12/09
Tang X et al. - In a trial to investigate potential molecular mechanisms underlying the antiangiogenic effect of non-nitrogen-containing and nitrogen-containing bisphosphonates, clodronate and pamidronate, respectively, in insulin-like growth factor (IGF)-1 responsive human breast cancer cells, it was demonstrated that pamidronate and clodronate functionally abrogated both in vitro and in vivo tumor angiogenesis induced by IGF-1-stimulated MCF-7 cells. These findings have highlighted an important mechanism of the pharmacological action of bisphosphonates in inhibition of tumor angiogenesis in breast cancer cells.
Methods
It was tested whether bisphosphonates had any effects on hypoxia-inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF) axis that plays a pivotal role in tumor angiogenesis.
Results
Both pamidronate and clodronate significantly suppressed IGF-1-induced HIF-1α protein accumulation and VEGF expression in MCF-7 cells.
Mechanistically, either pamidronate or clodronate did not affect mRNA expression of HIF-1α, but they apparently promoted the degradation of IGF-1-induced HIF-1α protein.
The presence of pamidronate and clodronate led to a dose-dependent decease in the newly-synthesized HIF-1α protein induced by IGF-1 in breast cancer cells after proteasomal inhibition, thus, indirectly reflecting inhibition of protein synthesis.
The inhibitory effects of bisphosphonates on the HIF-1α/VEGF axis are associated with inhibition of the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin signaling pathways.
Med Hypotheses. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Med%20Hypot heses.%27%29;) 2010 Jan 18. [Epub ahead of print]
Practical strategies for suppressing hypoxia-inducible factor activity in cancer therapy.
McCarty MF (http://www.ncbi.nlm.nih.gov/pubmed?term=%22McCarty%20MF%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Barroso-Aranda J (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Barroso-Aranda%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Contreras F (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Contreras%20F%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Oasis of Hope Hospital, Paseo Playas 19, Playas de Tijuana, Tijuana, B.C. 22504, Mexico.
The utility of anti-angiogenic strategies for cancer control is strongly compromised by hypoxia-driven phenotypic changes in cancer cells, which make cancer cells more invasive and more prone to give rise to metastases. A key mediator of this phenotypic shift is the transcription factor hypoxia-inducible factor-1 (HIF-1), which acts directly and indirectly to promote the epidermal-mesenchymal transition, boost cancer invasiveness, increase production of angiogenic factors, and induce chemoresistance. In some cancers, HIF-1 activity is constitutively elevated even in aerobic environments, making the cancer harder to treat and control. Practical strategies for suppressing HIF-1 activation may include the following: inhibiting NF-kappaB activation with salicylic acid and/or silibinin, which should decrease transcription of the HIF-1alpha gene; suppressing translation of HIF-1alpha mRNA with drugs that inhibit mTOR or topoisomerase I; supporting the effective activity of prolyl hydroxylases - which promote proteasomal degradation of HIF-1alpha under aerobic conditions - with antioxidant measures, alpha-ketoglutarate, and possibly dichloroacetate; promoting the O(2)-independent proteasomal degradation of HIF-1alpha with agents that inhibit the chaperone protein Hsp90; and blocking HIF-1 binding to its DNA response elements with anthracyclines. The utility of various combinations of these strategies should be tested in cancer cell cultures and rodent xenograft models; initial efforts in this regard have yielded encouraging results. Comprehensive strategies for suppressing HIF-1 activity can be expected to complement the efficacy of cancer chemotherapy and of effective anti-angiogenic regimens. Copyright © 2010 Elsevier Ltd. All rights reserved.
PMID: 20089365 [PubMed - as supplied by publisher]
J Pineal Res. 2009 May;46(4):415-21. Epub 2009 Mar 25.
Melatonin down-regulates HIF-1 alpha expression through inhibition of protein translation in prostate cancer cells.
Park JW (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Park%20JW%22[Author]&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Hwang MS (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Hwang%20MS%22[Author]&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Suh SI (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Suh%20SI%22[Author]&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Baek WK (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Baek%20WK%22[Author]&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Chronic Disease Research Center, School of Medicine, Keimyung University, Daegu, Korea.
Melatonin, the main secretory product of the pineal gland, has been shown to exert an oncostatic activity in cancer cells. Recently, several studies have shown that melatonin has antiangiogenic properties. However, the mechanism by which melatonin exerts antiangiogenenic effects is not understood. Hypoxia inducible factor (HIF)-1 is a transcription factor which mediates adaptive response to changes in tissue oxygenation. HIF-1 is a heterodimer formed by the association of a constitutively expressed HIF-1 beta subunit and a HIF-1 alpha subunit, the expression of which is highly regulated. In this study, pharmacologic concentrations of melatonin was found to inhibit expression of HIF-1 alpha protein under both normoxic and hypoxic conditions in DU145, PC-3, and LNCaP prostate cancer cells without affecting HIF-1 alpha mRNA levels. Consistent with the reduction in HIF-1 alpha protein levels, melatonin inhibited HIF-1 transcriptional activity and the release of vascular endothelial growth factor. We found that the suppression of HIF-1 alpha expression by melatonin correlated with dephosphorylation of p70S6K and its direct target RPS6, a pathway known to regulate HIF-1 alpha expression at the translational level. Metabolic labeling assays indicated that melatonin inhibits de novo synthesis of HIF-1 alpha protein. Taken together, these results suggest that the pharmacologic concentration of melatonin inhibits HIF-1 alpha expression through the suppression of protein translation in prostate cancer cells.
PMID: 19552765 [PubMed - indexed for MEDLINE]
<!-- / icon and title --> <!-- message --> A new way of treating cancer on the way? (http://www.nanomedicinecenter.com/article/a-new-way-of-treating-cancer-on-the-way/)
A team of scientists from the University of Toronto have found that, by modifying a protein that improves the process of preventing cancer growth, a new way of treating cancer is on the way. The protein they have been researching is called von Hippel-Lindau (VHL).
Tumors are known to have very low blood supply when they grow. Therefore, some parts — including the center of the tumor — have low levels of oxygen and are said to be hypoxic. Cells in these parts produce hypoxia-inducible factor (HIF) that makes it possible for them to keep on growing. Now, under normal conditions VHL degrades HIF — but VHL is deactivated when oxygen levels are low. So, in hypoxic regions of a tumour, just where VHL is needed to inhibit cancer, it is ineffective. That’s why scientists created a new type of VHL — a type that doesn’t stop working if oxygen levels are low.
“We have genetically removed the Achilles’ heel of VHL to permit unrestricted destruction of HIF,” said Michael Ohh, one of the researchers. “The level of HIF is usually very high under conditions of low oxygen but when we put in our bioengineered VHL its levels go right down to a level that would be comparable to that in normal oxygen levels.”
The details are published in EMBO Molecular Medicine.
Curr Opin Cell Biol. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Curr%20Opin %20Cell%20Biol.%27%29;) 2009 Dec 18. [Epub ahead of print]
Hypoxia-induced autophagy: cell death or cell survival?
Mazure NM (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Mazure%20NM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Pouysségur J (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Pouyss%C3%A9gur%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Institute of Developmental Biology and Cancer Research, University of Nice, CNRS-UMR 6543, Centre Antoine Lacassagne, 33 Avenue de Valombrose, 06189 Nice, France.
Hypoxia ( approximately 3-0.1% oxygen) is capable of rapidly inducing, via the hypoxia-inducible factor (HIF-1), a cell survival response engaging autophagy. This process is mediated by the atypical BH3-only proteins the Bcl-2/E1B 19kDa-interacting protein 3 (BNIP3/BNIP3L (NIX)) that are induced by HIF-1. These mitochondrial associated BNIP proteins also mediate mitophagy, a metabolic adaptation for survival that is able to control reactive oxygen species (ROS) production and DNA damage. In contrast, severe hypoxic conditions or anoxia (<0.1% oxygen), where the latter is often confused with physiological hypoxia, are capable of inducing a HIF-independent autophagic response, generated via an extreme nutritional stress response implicating the AMPK-mTOR and unfolded protein response (UPR) pathways. The autophagic cell death that is often observed in these extreme stress conditions should be seen as the outcome of failed adaptation. Copyright © 2009 Elsevier Ltd. All rights reserved.
PMID: 20022734 [PubMed - as supplied by publisher]
J Cell Mol Med. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27J%20Cell%20 Mol%20Med.%27%29;) 2009 Dec 8. [Epub ahead of print]
Tumor hypoxia induces a metabolic shift causing acidosis: a common feature in cancer.
Chiche J (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Chiche%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Brahimi-Horn MC (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Brahimi-Horn%20MC%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Pouysségur J (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Pouyss%C3%A9gur%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Institute of Developmental Biology and Cancer Research, University of Nice, CNRS UMR 6543, Centre A. Lacassagne, 33 Avenue Valombrose, 06189 Nice France.
Abstract Maintenance of cellular pH homeostasis is fundamental to life. A number of key intracellular pH (pHi) regulating systems including the Na(+)/H(+) exchangers (NHEs), the proton pump (V-ATPase), the monocarboxylate transporters (MCTs), the HCO(3) (-) transporters and exchangers (NBCs, AEs) and the membrane-associated and cytosolic carbonic anhydrases (CAs) cooperate in maintaining a pHi that is permissive for cell survival. A common feature of tumors is acidosis caused by hypoxia (low oxygen tension). In addition to oncogene activation and transformation, hypoxia is responsible for inducing acidosis through a shift in cellular metabolism that generates a high acid load in the tumor microenvironment. However, hypoxia and oncogene activation also allow cells to adapt to the potentially toxic effects of an excess in acidosis. Hypoxia does so by inducing the activity of a transcription factor the hypoxia-inducible factor (HIF), and particularly HIF-1, that in turn enhances the expression of a number of pHi-regulating systems that cope with acidosis. In this review we will focus on the characterization and function of some of the hypoxia-inducible pH-regulating systems and their induction by hypoxic stress. It is essential to understand the fundamentals of pH regulation to meet the challenge consisting in targeting tumor metabolism and acidosis as an anti-tumor approach. We will summarize strategies that take advantage of intracellular and extracellular pH regulation to target the primary tumor and metastatic growth, and to turn around resistance to chemotherapy and radiotherapy.
PMID: 20015196 [PubMed - as supplied by publisher]
(http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Curr%20Canc er%20Drug%20Targets.%27%29;)
Curr Cancer Drug Targets. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Curr%20Canc er%20Drug%20Targets.%27%29;) 2009 Nov;9(7):881-7.
HIF-1alpha and calcium signaling as targets for treatment of prostate cancer by cardiac glycosides.
Lin J (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Lin%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Denmeade S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Denmeade%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Carducci MA (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Carducci%20MA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Jefferson Kimmel Cancer Center, 834 Chestnut Street, Suite 314, Philadelphia, PA 19107, USA. Jianqing.lin@jefferson.edu
Prostate cancer possesses its unique feature of low proliferation rate and slow growth. Ca(2+)-induced apoptosis is not dependent on cell cycle progression and targeting this pathway could circumvent the problems encountered using current cytotoxic chemotherapies for prostate cancer. Hypoxia-inducible factor 1alpha (HIF-1alpha) is another novel cancer drug target and inhibitors of hypoxia-response pathway are being developed. Digoxin and other cardiac glycosides, known inhibitors of the alpha-subunit of sarcolemmal Na(+)K(+)-ATPase, were recently found to block tumor growth via the inhibition of HIF-1alpha synthesis. Thus, cardiac glycosides disrupt two important cellular pathways and, therefore, may be useful as an anticancer therapy. This review will focus on HIF-1alpha and calcium signaling as novel cancer drug targets in prostate cancer. The possible application of digoxin and other cardiac glycosides in cancer therapeutics especially in prostate cancer is discussed.
PMID: 20025575 [PubMed - in process]
Ann N Y Acad Sci. (http://javascript%3cb%3e%3c/b%3E:AL_get%28this,%20%27jour%27,%20%27Ann%20N%20Y %20Acad%20Sci.%27%29;) 2009 Oct;1177:2-8.
Regulation of vascularization by hypoxia-inducible factor 1.
Semenza GL (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Semenza%20GL%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Vascular Program, Institute for Cell Engineering; McKusick-Nathans Institute of Genetic Medicine, Baltimore, Maryland 21205, USA. gsemenza@jhmi.edu
Vascularization and vascular remodeling represent critical adaptive responses to tissue hypoxia that are mediated by hypoxia-inducible factor 1 (HIF-1). In patients with peripheral arterial disease, these responses are impaired by aging and diabetes, leading to critical limb ischemia and amputation. Intramuscular injection of an adenovirus encoding a constitutively active form of the HIF-1alpha subunit (CA5) increases the recovery of blood flow following femoral artery ligation in a mouse model of age-dependent critical limb ischemia. Intradermal injection of a plasmid encoding CA5 promotes healing of cutaneous wounds in a mouse model of diabetes. In cancer, vascularization is required for tumors to grow beyond microscopic size, a process that involves HIF-1-dependent production of angiogenic growth factors. Daily treatment of prostate cancer xenograft-bearing mice with low-dose anthracycline (doxorubicin or daunorubicin) chemotherapy inhibits HIF-1 DNA-binding activity, HIF-1-dependent expression of angiogenic growth factors, mobilization of circulating angiogenic cells, and tumor vascularization, thereby arresting tumor growth.
PMID: 19845601 [PubMed - indexed for MEDLINE]
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J Natl Cancer Inst. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27J%20Natl%20 Cancer%20Inst.%27%29;) 2009 Mar 18;101(6):368-70. Epub 2009 Mar 10.
Low-dose anthracyclines may block HIF-1 and stop tumor growth.
Hede K (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Hede%20K%22%5BAuthor%5D).
PMID: 19276456 [PubMed - indexed for MEDLINE]Free Article
http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--highwire.stanford.edu-icons-externalservices-pubmed-custom-oxfordjournals_final_free.gif (http://jnci.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=19276456)
Includes inset "Digoxin as Anticancer Agent: The HIF-1 Connection"
A recent study suggests that the well-known anthracycline chemotherapeutic<sup> </sup>agents doxorubicin and daunorubicin, when given in small doses,<sup> </sup>can reduce tumor vascularization in animal models. The discovery,<sup> </sup>by Gregg Semenza, M.D., Ph.D., and his colleagues at Johns Hopkins<sup> </sup>University School of Medicine in Baltimore, reveals a new mechanism<sup> </sup>of action for these mainstays of chemotherapy and explains why<sup> </sup>smaller doses of chemotherapy agents given over a longer period<sup> </sup>can sometimes inhibit formation of new blood vessels.<sup> </sup>
Anthracyclines kill cancer cells by interfering with DNA replication<sup> </sup>in actively dividing cells. But Semenza and his colleagues demonstrate<sup> </sup>that the drugs also interfere with a key regulator of oxygen<sup> </sup>metabolism, hypoxia-inducible factor 1 (HIF-1), a crucial regulator<sup> </sup>of vascularization.<sup> </sup>
Semenza discovered HIF-1 in 1992 in cells grown in low-oxygen<sup> </sup>(hypoxic) conditions and demonstrated that HIF-1 regulated the<sup> </sup>adaptation to the hypoxic growth conditions common in many solid<sup> </sup>tumors. HIF-1, a transcription factor, is a master regulator<sup> </sup>that activates vascular endothelial growth factor (VEGF) and<sup> </sup>many other adaptive proteins, allowing cells to generate fuel<sup> </sup>under hypoxic conditions.<sup> </sup>
In the present study, published in late January 2009 in the<sup> </sup>Proceedings of the National Academy of Sciences online edition,<sup> </sup>he shows that chronic inhibition of HIF-1 can effectively block<sup> </sup>tumor growth by blocking angiogenesis in a mouse xenograft model.<sup> </sup>
"When we treat [mice] with these drugs, almost immediately we<sup> </sup>inhibit HIF-1 activity, we inhibit the production of angiogenic<sup> </sup>cytokines such as VEGF, we inhibit the mobilization of angiogenic<sup> </sup>cells into the circulation, and we block tumor vascularization,"<sup> </sup>said Semenza. "At least in these xenograft models, when you<sup> </sup>block tumor vascularization, you block tumor growth."<sup> </sup>
Master Regulator
In recent years, HIF-1 has emerged as a critical regulator of<sup> </sup>cancer growth, progression, and metastasis. High HIF-1 levels<sup> </sup>in tumor cells have been linked to poor patient outcomes in<sup> </sup>bladder, breast, cervical, endometrial, lung, and pancreatic<sup> </sup>cancers, among others. HIF-1 enables tumor cells to thrive under<sup> </sup>the hypoxic conditions that have been the bane of oncologists<sup> </sup>trying to wipe out cancer cells remaining after radiation and<sup> </sup>chemotherapy.
Mol Carcinog. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Mol%20Carci nog.%27%29;) 2009 Oct 12. [Epub ahead of print]
Aryl hydrocarbon nuclear translocator (hypoxia inducible factor 1beta) activity is required more during early than late tumor growth.
Shi S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Shi%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Yoon DY (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Yoon%20DY%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Hodge-Bell K (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Hodge-Bell%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Huerta-Yepez S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Huerta-Yepez%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Hankinson O (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Hankinson%20O%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California.
c4 is a derivative of the mouse hepatoma cell line, Hepa-1, that harbors a mutation in the aryl hydrocarbon receptor nuclear translocator gene (Arnt, or hypoxia inducible factor 1beta [HIF-1beta]) leading to loss of activity. Clone 3 cells were generated by introducing a doxycycline-repressible Arnt expression vector into c4 cells. Clone 3 cells were injected subcutaneously into immunosuppressed mice, which were treated with doxycyline (a) throughout the growth of the subsequent tumor xenografts, or (b) from day 7 through to the end of the experiment (day 30), or not treated (c). Tumors in all groups grew exponentially between days 14 and 30, and at rates that were indistinguishable from each other. However, tumors in group a were smaller than those of the other two groups throughout the measurable growth period, while tumor volumes in groups b and c were not significantly different from each other. The degrees of vascularity and apoptosis did not correlate with the differences in degrees of growth between the different groups. Thus, Arnt is required during the early stages of growth of the tumors but less in later stages. Since Arnt does not detectably effect the growth kinetics of Hepa-1 cells either during hypoxia or normoxia, this requirement is unlikely to reflect a direct effect of Arnt on cell proliferation, and is therefore probably a consequence of altered interaction(s) between the tumor cells and the host. These studies suggest that Arnt (and HIF-1alpha/HIF-2alpha) inhibitors will be particularly effective against smaller tumors, including micrometastases. (c) 2009 Wiley-Liss, Inc.
PMID: 19824022 [PubMed - as supplied by publisher]
HIF-1alpha and Cancer Therapy.
Koh MY (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Koh%20MY%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Spivak-Kroizman TR (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Spivak-Kroizman%20TR%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Powis G (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Powis%20G%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Most solid tumors develop regions of hypoxia as they grow and outstrip their blood supply. In order to survive in the stressful hypoxic environment, tumor cells have developed a coordinated set of responses orchestrating their adaptation to hypoxia. The outcomes of the cellular responses to hypoxia are aggressive disease, resistance to therapy, and decreased patient survival. A critical mediator of the hypoxic response is the transcription factor hypoxia-inducible factor 1 (HIF-1) that upregulates expression of proteins that promote angiogenesis, anaerobic metabolism, and many other survival pathways. Regulation of HIF-1alpha, a component of the HIF-1 heterodimer, occurs at multiple levels including translation, degradation, and transcriptional activation, and serves as a testimony to the central role of HIF-1. Studies demonstrating the importance of HIF-1alpha expression for tumor survival have made HIF-1alpha an attractive target for cancer therapy. The growing l.ist of pharmacological inhibitors of HIF-1 and their varied targets mirrors the complex molecular mechanisms controlling HIF-1. In this chapter, we summarize recent findings regarding the regulation of HIF-1alpha and the progress made in identifying new therapeutic agents that inhibit HIF-1alpha.
PMID: 20033376 [PubMed - as supplied by publisher]
Proc Natl Acad Sci U S A. (http://javascript%3cb%3e%3c/b%3E:AL_get%28this,%20%27jour%27,%20%27Proc%20Natl %20Acad%20Sci%20U%20S%20A.%27%29;) 2009 Dec 15;106(50):21306-11. Epub 2009 Dec 2.
Human cancers converge at the HIF-2{alpha} oncogenic axis.
Franovic A (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Franovic%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Holterman CE (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Holterman%20CE%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Payette J (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Payette%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Lee S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Lee%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
Cancer development is a multistep process, driven by a series of genetic and environmental alterations, that endows cells with a set of hallmark traits required for tumorigenesis. It is broadly accepted that growth signal autonomy, the first hallmark of malignancies, can be acquired through multiple genetic mutations that activate an array of complex, cancer-specific growth circuits [Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57-70; Vogelstein B, Kinzler KW (2004) Cancer genes and the pathways they control. Nat Med 10:789-799]. The superfluous nature of these pathways is thought to severely limit therapeutic approaches targeting tumor proliferation, and it has been suggested that this strategy be abandoned in favor of inhibiting more systemic hallmarks, including angiogenesis (Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: Mechanisms of anti-tumor activity. Nat Rev Cancer 8:579-591; Stommel JM, et al. (2007) Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318:287-290; Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727-739; Kaiser J (2008) Cancer genetics: A detailed genetic portrait of the deadliest human cancers. Science 321:1280-1281]. Here, we report the unexpected observation that genetically diverse cancers converge at a common and obligatory growth axis instigated by HIF-2alpha, an element of the oxygen-sensing machinery. Inhibition of HIF-2alpha prevents the in vivo growth and tumorigenesis of highly aggressive glioblastoma, colorectal, and non-small-cell lung carcinomas and the in vitro autonomous proliferation of several others, regardless of their mutational status and tissue of origin. The concomitant deactivation of select receptor tyrosine kinases, including the EGFR and IGF1R, as well as downstream ERK/Akt signaling, suggests that HIF-2alpha exerts its proliferative effects by endorsing these major pathways. Consistently, silencing these receptors phenocopies the loss of HIF-2alpha oncogenic activity, abrogating the serum-independent growth of human cancer cells in culture. Based on these data, we propose an alternative to the predominant view that cancers exploit independent autonomous growth pathways and reveal HIF-2alpha as a potentially universal culprit in promoting the persistent proliferation of neoplastic cells.
PMID: 19955413 [PubMed - in process]
Breast Cancer Res. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Breast%20Ca ncer%20Res.%27%29;) 2009;11(6):R84. Epub 2009 Nov 17.
Hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression in circulating tumor cells of breast cancer patients.
Kallergi G (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Kallergi%20G%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Markomanolaki H (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Markomanolaki%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Giannoukaraki V (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Giannoukaraki%20V%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Papadaki MA (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Papadaki%20MA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Strati A (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Strati%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Lianidou ES (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Lianidou%20ES%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Georgoulias V (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Georgoulias%20V%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Mavroudis D (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Mavroudis%20D%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Agelaki S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Agelaki%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Voutes, Heraklion, 71110, Greece. kalergi@med.uoc.gr
Abstract
Introduction
The detection of peripheral blood circulating tumor cells (CTCs) and bone marrow disseminated tumor cells (DTCs) in breast cancer patients is associated with a high incidence of disease relapse and disease-related death. Since hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) play an important role in angiogenesis and tumor progression, the purpose of the current study was to investigate their expression in CTCs.
Methods
The expression of cytokeratins (CK), VEGF, vascular endothelial growth factor receptor-2 (VEGFR2), HIF-1α and phosphorylated-focal adhesion kinase (pFAK) in CTCs from 34 patients with metastatic breast cancer who had detectable CK-19 mRNA-positive CTCs was assessed using double staining experiments and confocal laser scanning microscopy. Peripheral blood mononuclear cells (PBMCs) were stained with a monoclonal A45-B/B3 pancytokeratin antibody in combination with either VEGF or VEGFR2 or HIF-1α or pFAK antibodies, respectively.
Results
pFAK expression in CTCs was detected in 92% of patients whereas expression of VEGF, VEGFR2 and HIF-1α was observed in 62%, 47% and 76% of patients, respectively. VEGF, VEGFR2, HIF-1α and pFAK were expressed in 73%, 71%, 56% and 81%, respectively, of all the detected CTCs. VEGF mRNA was also detected by quantitative real-time RT-PCR in immunomagnetically-separated CTCs. Double and 3 triple staining experiments in cytospins of immunomagnetically-isolated CTCs showed that VEGF co-expressed with HIF-1α and VEGFR2.
Conclusions
The expression of pFAK, HIF-1α, VEGF and VEGFR2 in CTCs of patients with metastatic breast cancer could explain the metastatic potential of these cells and may provide a therapeutic target for their elimination.
PMID: 19919679 [PubMed - in process]
British Journal of Cancer (2010) 102, 789–795. doi:10.1038/sj.bjc.6605551 www.bjcancer.com (http://www.bjcancer.com/)
Published online 26 January 2010
Hypoxia inducible factors in cancer stem cells
J M Heddleston<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605551a.html#aff1)</sup>, Z Li<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605551a.html#aff1)</sup>, J D Lathia<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605551a.html#aff1)</sup>, S Bao<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605551a.html#aff1)</sup>, A B Hjelmeland<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605551a.html#aff1)</sup> and J N Rich<sup>1 (http://www.nature.com/bjc/journal/v102/n5/abs/6605551a.html#aff1)</sup>
<sup>1</sup>Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland 44195, OH, USA
Correspondence: Professor JN Rich, E-mail: richj@ccf.org
Received 14 October 2009; Revised 8 December 2009; Accepted 22 December 2009; Published online 26 January 2010.
Top of page (http://www.nature.com/bjc/journal/v102/n5/abs/6605551a.html#top) Abstract
Oxygen is an essential regulator of cellular metabolism, survival, and proliferation. Cellular responses to oxygen levels are monitored, in part, by the transcriptional activity of the hypoxia inducible factors (HIFs). Under hypoxia, HIFs regulate a variety of pro-angiogenic and pro-glycolysis pathways. In solid cancers, regions of hypoxia are commonly present throughout the tissue because of the chaotic vascular architecture and regions of necrosis. In these regions, the hypoxic state fluctuates in a spatial and temporal manner. Transient hypoxic cycling causes an increase in the activity of the HIF proteins above what is typical for non-pathologic tissue. The extent of hypoxia strongly correlates to poor patient survival, therapeutic resistance and an aggressive tumour phenotype, but the full contribution of hypoxia and the HIFs to tumour biology is an area of active investigation. Recent reports link resistance to conventional therapies and the metastatic potential to a stem-like tumour population, termed cancer stem cells (CSCs). We and others have shown that within brain tumours CSCs reside in two niches, a perivascular location and the surrounding necrotic tissue. Restricted oxygen conditions increase the CSC fraction and promote acquisition of a stem-like state. Cancer stem cells are critically dependant on the HIFs for survival, self-renewal, and tumour growth. These observations and those from normal stem cell biology provide a new mechanistic explanation for the contribution of hypoxia to malignancy. Further, the presence of hypoxia in tumours may present challenges for therapy because of the promotion of CSC phenotypes even upon successful killing of CSCs. The current experimental evidence suggests that CSCs are plastic cell states governed by microenvironmental conditions, such as hypoxia, that may be critical for the development of new therapies targeted to disrupt the microenvironment.
Cancer Res. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Cancer%20Re s.%27%29;) 2009 Sep 15;69(18):7160-4. Epub 2009 Sep 8.
mTOR signal and hypoxia-inducible factor-1 alpha regulate CD133 expression in cancer cells.
Matsumoto K (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Matsumoto%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Arao T (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Arao%20T%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Tanaka K (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Tanaka%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Kaneda H (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Kaneda%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Kudo K (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Kudo%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Fujita Y (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Fujita%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Tamura D (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Tamura%20D%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Aomatsu K (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Aomatsu%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Tamura T (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Tamura%20T%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Yamada Y (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Yamada%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Saijo N (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Saijo%20N%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Nishio K (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Nishio%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
The underlying mechanism regulating the expression of the cancer stem cell/tumor-initiating cell marker CD133/prominin-1 in cancer cells remains largely unclear, although knowledge of this mechanism would likely provide important biological information regarding cancer stem cells. Here, we found that the inhibition of mTOR signaling up-regulated CD133 expression at both the mRNA and protein levels in a CD133-overexpressing cancer cell line. This effect was canceled by a rapamycin-competitor, tacrolimus, and was not modified by conventional cytotoxic drugs. We hypothesized that hypoxia-inducible factor-1 alpha (HIF-1 alpha), a downstream molecule in the mTOR signaling pathway, might regulate CD133 expression; we therefore investigated the relation between CD133 and HIF-1 alpha. Hypoxic conditions up-regulated HIF-1 alpha expression and inversely down-regulated CD133 expression at both the mRNA and protein levels. Similarly, the HIF-1 alpha activator deferoxamine mesylate dose-dependently down-regulated CD133 expression, consistent with the effects of hypoxic conditions. Finally, the correlations between CD133 and the expressions of HIF-1 alpha and HIF-1 beta were examined using clinical gastric cancer samples. A strong inverse correlation (r = -0.68) was observed between CD133 and HIF-1 alpha, but not between CD133 and HIF-1 beta. In conclusion, these results indicate that HIF-1 alpha down-regulates CD133 expression and suggest that mTOR signaling is involved in the expression of CD133 in cancer cells. Our findings provide a novel insight into the regulatory mechanisms of CD133 expression via mTOR signaling and HIF-1 alpha in cancer cells and might lead to insights into the involvement of the mTOR signal and oxygen-sensitive intracellular pathways in the maintenance of stemness in cancer stem cells.
PMID: 19738050 [PubMed - indexed for MEDLINE]
Br J Cancer. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Br%20J%20Ca ncer.%27%29;). [Epub ahead of print]
Hypoxia potentiates Notch signaling in breast cancer leading to decreased E-cadherin expression and increased cell migration and invasion.
Chen J (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Chen%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Imanaka N (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Imanaka%20N%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Chen J (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Chen%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Griffin JD (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Griffin%20JD%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Background:Epithelial-to-mesenchymal transition (EMT) is associated with decreased adhesion and acquisition of metastatic potential of breast cancer cells. Epithelial-to-mesenchymal transition is mediated, in part, by two transcription repressors, Snail and Slug, that are known to be targets of the Notch signaling pathway, and JAGGED1-induced Notch activation increases EMT. However, the events that lead to increased Notch activity during EMT of breast cancer cells are unknown. Methods: The accumulation of hypoxia inducible factors (HIFs) under hypoxia was detected by western blot analysis, and their effects on Notch signaling were measured by an in vitro Notch reporter assay. The expression of Notch target genes under hypoxia was tested by real-time PCR. The knockdown of HIF-1alpha was mediated by retroviral delivery of shRNA. The expression of Slug and Snail under hypoxia was measured by real-time PCR. Breast cancer cell migration and invasion under hypoxia were tested with cell migration and invasion kits.Results:Hypoxia increased the expression of Notch target genes such as HES1 and HEY1 in breast cancer cells, as was expression of Notch receptors and ligands. The mechanism is likely to involve the accumulation of HIF-1alpha and HIF-2alpha in these cells by hypoxia, which synergised with the Notch co-activator MAML1 in potentiating Notch activity. Hypoxia inducible factor-1alpha was found to bind to HES1 promoter under hypoxia. Knockdown of HIF-1alpha with shRNA inhibited both HES1 and HEY1 expression under hypoxia. Hypoxia increased the expression of Slug and Snail, and decreased the expression of E-cadherin, hallmarks of EMT. Notch pathway inhibition abrogated the hypoxia-mediated increase in Slug and Snail expression, as well as decreased breast cancer cell migration and invasion. Conclusion:Hypoxia-mediated Notch signaling may have an important role in the initiation of EMT and subsequent potential for breast cancer metastasis. British Journal of Cancer advance online publication, 15 December 2009; doi:10.1038/sj.bjc.6605486 www.bjcancer.com (http://www.bjcancer.com).
PMID: 20010940 [PubMed - as supplied by publisher]
LINK (http://her2support.org/vbulletin/showthread.php?p=204345&highlight=hypoxia-inducible+factor#post204345) to cancer stem cell thread
Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1α/VEGF signaling pathways in human breast cancer cells (http://www.mdlinx.com/readArticle.cfm?art_id=2835257)
International Journal of Cancer, 08/12/09
Tang X et al. - In a trial to investigate potential molecular mechanisms underlying the antiangiogenic effect of non-nitrogen-containing and nitrogen-containing bisphosphonates, clodronate and pamidronate, respectively, in insulin-like growth factor (IGF)-1 responsive human breast cancer cells, it was demonstrated that pamidronate and clodronate functionally abrogated both in vitro and in vivo tumor angiogenesis induced by IGF-1-stimulated MCF-7 cells. These findings have highlighted an important mechanism of the pharmacological action of bisphosphonates in inhibition of tumor angiogenesis in breast cancer cells.
Methods
It was tested whether bisphosphonates had any effects on hypoxia-inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF) axis that plays a pivotal role in tumor angiogenesis.
Results
Both pamidronate and clodronate significantly suppressed IGF-1-induced HIF-1α protein accumulation and VEGF expression in MCF-7 cells.
Mechanistically, either pamidronate or clodronate did not affect mRNA expression of HIF-1α, but they apparently promoted the degradation of IGF-1-induced HIF-1α protein.
The presence of pamidronate and clodronate led to a dose-dependent decease in the newly-synthesized HIF-1α protein induced by IGF-1 in breast cancer cells after proteasomal inhibition, thus, indirectly reflecting inhibition of protein synthesis.
The inhibitory effects of bisphosphonates on the HIF-1α/VEGF axis are associated with inhibition of the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin signaling pathways.
Med Hypotheses. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Med%20Hypot heses.%27%29;) 2010 Jan 18. [Epub ahead of print]
Practical strategies for suppressing hypoxia-inducible factor activity in cancer therapy.
McCarty MF (http://www.ncbi.nlm.nih.gov/pubmed?term=%22McCarty%20MF%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Barroso-Aranda J (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Barroso-Aranda%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Contreras F (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Contreras%20F%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Oasis of Hope Hospital, Paseo Playas 19, Playas de Tijuana, Tijuana, B.C. 22504, Mexico.
The utility of anti-angiogenic strategies for cancer control is strongly compromised by hypoxia-driven phenotypic changes in cancer cells, which make cancer cells more invasive and more prone to give rise to metastases. A key mediator of this phenotypic shift is the transcription factor hypoxia-inducible factor-1 (HIF-1), which acts directly and indirectly to promote the epidermal-mesenchymal transition, boost cancer invasiveness, increase production of angiogenic factors, and induce chemoresistance. In some cancers, HIF-1 activity is constitutively elevated even in aerobic environments, making the cancer harder to treat and control. Practical strategies for suppressing HIF-1 activation may include the following: inhibiting NF-kappaB activation with salicylic acid and/or silibinin, which should decrease transcription of the HIF-1alpha gene; suppressing translation of HIF-1alpha mRNA with drugs that inhibit mTOR or topoisomerase I; supporting the effective activity of prolyl hydroxylases - which promote proteasomal degradation of HIF-1alpha under aerobic conditions - with antioxidant measures, alpha-ketoglutarate, and possibly dichloroacetate; promoting the O(2)-independent proteasomal degradation of HIF-1alpha with agents that inhibit the chaperone protein Hsp90; and blocking HIF-1 binding to its DNA response elements with anthracyclines. The utility of various combinations of these strategies should be tested in cancer cell cultures and rodent xenograft models; initial efforts in this regard have yielded encouraging results. Comprehensive strategies for suppressing HIF-1 activity can be expected to complement the efficacy of cancer chemotherapy and of effective anti-angiogenic regimens. Copyright © 2010 Elsevier Ltd. All rights reserved.
PMID: 20089365 [PubMed - as supplied by publisher]
J Pineal Res. 2009 May;46(4):415-21. Epub 2009 Mar 25.
Melatonin down-regulates HIF-1 alpha expression through inhibition of protein translation in prostate cancer cells.
Park JW (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Park%20JW%22[Author]&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Hwang MS (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Hwang%20MS%22[Author]&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Suh SI (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Suh%20SI%22[Author]&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Baek WK (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Baek%20WK%22[Author]&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Chronic Disease Research Center, School of Medicine, Keimyung University, Daegu, Korea.
Melatonin, the main secretory product of the pineal gland, has been shown to exert an oncostatic activity in cancer cells. Recently, several studies have shown that melatonin has antiangiogenic properties. However, the mechanism by which melatonin exerts antiangiogenenic effects is not understood. Hypoxia inducible factor (HIF)-1 is a transcription factor which mediates adaptive response to changes in tissue oxygenation. HIF-1 is a heterodimer formed by the association of a constitutively expressed HIF-1 beta subunit and a HIF-1 alpha subunit, the expression of which is highly regulated. In this study, pharmacologic concentrations of melatonin was found to inhibit expression of HIF-1 alpha protein under both normoxic and hypoxic conditions in DU145, PC-3, and LNCaP prostate cancer cells without affecting HIF-1 alpha mRNA levels. Consistent with the reduction in HIF-1 alpha protein levels, melatonin inhibited HIF-1 transcriptional activity and the release of vascular endothelial growth factor. We found that the suppression of HIF-1 alpha expression by melatonin correlated with dephosphorylation of p70S6K and its direct target RPS6, a pathway known to regulate HIF-1 alpha expression at the translational level. Metabolic labeling assays indicated that melatonin inhibits de novo synthesis of HIF-1 alpha protein. Taken together, these results suggest that the pharmacologic concentration of melatonin inhibits HIF-1 alpha expression through the suppression of protein translation in prostate cancer cells.
PMID: 19552765 [PubMed - indexed for MEDLINE]
<!-- / icon and title --> <!-- message --> A new way of treating cancer on the way? (http://www.nanomedicinecenter.com/article/a-new-way-of-treating-cancer-on-the-way/)
A team of scientists from the University of Toronto have found that, by modifying a protein that improves the process of preventing cancer growth, a new way of treating cancer is on the way. The protein they have been researching is called von Hippel-Lindau (VHL).
Tumors are known to have very low blood supply when they grow. Therefore, some parts — including the center of the tumor — have low levels of oxygen and are said to be hypoxic. Cells in these parts produce hypoxia-inducible factor (HIF) that makes it possible for them to keep on growing. Now, under normal conditions VHL degrades HIF — but VHL is deactivated when oxygen levels are low. So, in hypoxic regions of a tumour, just where VHL is needed to inhibit cancer, it is ineffective. That’s why scientists created a new type of VHL — a type that doesn’t stop working if oxygen levels are low.
“We have genetically removed the Achilles’ heel of VHL to permit unrestricted destruction of HIF,” said Michael Ohh, one of the researchers. “The level of HIF is usually very high under conditions of low oxygen but when we put in our bioengineered VHL its levels go right down to a level that would be comparable to that in normal oxygen levels.”
The details are published in EMBO Molecular Medicine.
Curr Opin Cell Biol. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Curr%20Opin %20Cell%20Biol.%27%29;) 2009 Dec 18. [Epub ahead of print]
Hypoxia-induced autophagy: cell death or cell survival?
Mazure NM (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Mazure%20NM%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Pouysségur J (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Pouyss%C3%A9gur%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Institute of Developmental Biology and Cancer Research, University of Nice, CNRS-UMR 6543, Centre Antoine Lacassagne, 33 Avenue de Valombrose, 06189 Nice, France.
Hypoxia ( approximately 3-0.1% oxygen) is capable of rapidly inducing, via the hypoxia-inducible factor (HIF-1), a cell survival response engaging autophagy. This process is mediated by the atypical BH3-only proteins the Bcl-2/E1B 19kDa-interacting protein 3 (BNIP3/BNIP3L (NIX)) that are induced by HIF-1. These mitochondrial associated BNIP proteins also mediate mitophagy, a metabolic adaptation for survival that is able to control reactive oxygen species (ROS) production and DNA damage. In contrast, severe hypoxic conditions or anoxia (<0.1% oxygen), where the latter is often confused with physiological hypoxia, are capable of inducing a HIF-independent autophagic response, generated via an extreme nutritional stress response implicating the AMPK-mTOR and unfolded protein response (UPR) pathways. The autophagic cell death that is often observed in these extreme stress conditions should be seen as the outcome of failed adaptation. Copyright © 2009 Elsevier Ltd. All rights reserved.
PMID: 20022734 [PubMed - as supplied by publisher]
J Cell Mol Med. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27J%20Cell%20 Mol%20Med.%27%29;) 2009 Dec 8. [Epub ahead of print]
Tumor hypoxia induces a metabolic shift causing acidosis: a common feature in cancer.
Chiche J (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Chiche%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Brahimi-Horn MC (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Brahimi-Horn%20MC%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Pouysségur J (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Pouyss%C3%A9gur%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Institute of Developmental Biology and Cancer Research, University of Nice, CNRS UMR 6543, Centre A. Lacassagne, 33 Avenue Valombrose, 06189 Nice France.
Abstract Maintenance of cellular pH homeostasis is fundamental to life. A number of key intracellular pH (pHi) regulating systems including the Na(+)/H(+) exchangers (NHEs), the proton pump (V-ATPase), the monocarboxylate transporters (MCTs), the HCO(3) (-) transporters and exchangers (NBCs, AEs) and the membrane-associated and cytosolic carbonic anhydrases (CAs) cooperate in maintaining a pHi that is permissive for cell survival. A common feature of tumors is acidosis caused by hypoxia (low oxygen tension). In addition to oncogene activation and transformation, hypoxia is responsible for inducing acidosis through a shift in cellular metabolism that generates a high acid load in the tumor microenvironment. However, hypoxia and oncogene activation also allow cells to adapt to the potentially toxic effects of an excess in acidosis. Hypoxia does so by inducing the activity of a transcription factor the hypoxia-inducible factor (HIF), and particularly HIF-1, that in turn enhances the expression of a number of pHi-regulating systems that cope with acidosis. In this review we will focus on the characterization and function of some of the hypoxia-inducible pH-regulating systems and their induction by hypoxic stress. It is essential to understand the fundamentals of pH regulation to meet the challenge consisting in targeting tumor metabolism and acidosis as an anti-tumor approach. We will summarize strategies that take advantage of intracellular and extracellular pH regulation to target the primary tumor and metastatic growth, and to turn around resistance to chemotherapy and radiotherapy.
PMID: 20015196 [PubMed - as supplied by publisher]
(http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Curr%20Canc er%20Drug%20Targets.%27%29;)
Curr Cancer Drug Targets. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Curr%20Canc er%20Drug%20Targets.%27%29;) 2009 Nov;9(7):881-7.
HIF-1alpha and calcium signaling as targets for treatment of prostate cancer by cardiac glycosides.
Lin J (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Lin%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Denmeade S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Denmeade%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Carducci MA (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Carducci%20MA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Jefferson Kimmel Cancer Center, 834 Chestnut Street, Suite 314, Philadelphia, PA 19107, USA. Jianqing.lin@jefferson.edu
Prostate cancer possesses its unique feature of low proliferation rate and slow growth. Ca(2+)-induced apoptosis is not dependent on cell cycle progression and targeting this pathway could circumvent the problems encountered using current cytotoxic chemotherapies for prostate cancer. Hypoxia-inducible factor 1alpha (HIF-1alpha) is another novel cancer drug target and inhibitors of hypoxia-response pathway are being developed. Digoxin and other cardiac glycosides, known inhibitors of the alpha-subunit of sarcolemmal Na(+)K(+)-ATPase, were recently found to block tumor growth via the inhibition of HIF-1alpha synthesis. Thus, cardiac glycosides disrupt two important cellular pathways and, therefore, may be useful as an anticancer therapy. This review will focus on HIF-1alpha and calcium signaling as novel cancer drug targets in prostate cancer. The possible application of digoxin and other cardiac glycosides in cancer therapeutics especially in prostate cancer is discussed.
PMID: 20025575 [PubMed - in process]
Ann N Y Acad Sci. (http://javascript%3cb%3e%3c/b%3E:AL_get%28this,%20%27jour%27,%20%27Ann%20N%20Y %20Acad%20Sci.%27%29;) 2009 Oct;1177:2-8.
Regulation of vascularization by hypoxia-inducible factor 1.
Semenza GL (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Semenza%20GL%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Vascular Program, Institute for Cell Engineering; McKusick-Nathans Institute of Genetic Medicine, Baltimore, Maryland 21205, USA. gsemenza@jhmi.edu
Vascularization and vascular remodeling represent critical adaptive responses to tissue hypoxia that are mediated by hypoxia-inducible factor 1 (HIF-1). In patients with peripheral arterial disease, these responses are impaired by aging and diabetes, leading to critical limb ischemia and amputation. Intramuscular injection of an adenovirus encoding a constitutively active form of the HIF-1alpha subunit (CA5) increases the recovery of blood flow following femoral artery ligation in a mouse model of age-dependent critical limb ischemia. Intradermal injection of a plasmid encoding CA5 promotes healing of cutaneous wounds in a mouse model of diabetes. In cancer, vascularization is required for tumors to grow beyond microscopic size, a process that involves HIF-1-dependent production of angiogenic growth factors. Daily treatment of prostate cancer xenograft-bearing mice with low-dose anthracycline (doxorubicin or daunorubicin) chemotherapy inhibits HIF-1 DNA-binding activity, HIF-1-dependent expression of angiogenic growth factors, mobilization of circulating angiogenic cells, and tumor vascularization, thereby arresting tumor growth.
PMID: 19845601 [PubMed - indexed for MEDLINE]
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J Natl Cancer Inst. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27J%20Natl%20 Cancer%20Inst.%27%29;) 2009 Mar 18;101(6):368-70. Epub 2009 Mar 10.
Low-dose anthracyclines may block HIF-1 and stop tumor growth.
Hede K (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Hede%20K%22%5BAuthor%5D).
PMID: 19276456 [PubMed - indexed for MEDLINE]Free Article
http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--highwire.stanford.edu-icons-externalservices-pubmed-custom-oxfordjournals_final_free.gif (http://jnci.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=19276456)
Includes inset "Digoxin as Anticancer Agent: The HIF-1 Connection"
A recent study suggests that the well-known anthracycline chemotherapeutic<sup> </sup>agents doxorubicin and daunorubicin, when given in small doses,<sup> </sup>can reduce tumor vascularization in animal models. The discovery,<sup> </sup>by Gregg Semenza, M.D., Ph.D., and his colleagues at Johns Hopkins<sup> </sup>University School of Medicine in Baltimore, reveals a new mechanism<sup> </sup>of action for these mainstays of chemotherapy and explains why<sup> </sup>smaller doses of chemotherapy agents given over a longer period<sup> </sup>can sometimes inhibit formation of new blood vessels.<sup> </sup>
Anthracyclines kill cancer cells by interfering with DNA replication<sup> </sup>in actively dividing cells. But Semenza and his colleagues demonstrate<sup> </sup>that the drugs also interfere with a key regulator of oxygen<sup> </sup>metabolism, hypoxia-inducible factor 1 (HIF-1), a crucial regulator<sup> </sup>of vascularization.<sup> </sup>
Semenza discovered HIF-1 in 1992 in cells grown in low-oxygen<sup> </sup>(hypoxic) conditions and demonstrated that HIF-1 regulated the<sup> </sup>adaptation to the hypoxic growth conditions common in many solid<sup> </sup>tumors. HIF-1, a transcription factor, is a master regulator<sup> </sup>that activates vascular endothelial growth factor (VEGF) and<sup> </sup>many other adaptive proteins, allowing cells to generate fuel<sup> </sup>under hypoxic conditions.<sup> </sup>
In the present study, published in late January 2009 in the<sup> </sup>Proceedings of the National Academy of Sciences online edition,<sup> </sup>he shows that chronic inhibition of HIF-1 can effectively block<sup> </sup>tumor growth by blocking angiogenesis in a mouse xenograft model.<sup> </sup>
"When we treat [mice] with these drugs, almost immediately we<sup> </sup>inhibit HIF-1 activity, we inhibit the production of angiogenic<sup> </sup>cytokines such as VEGF, we inhibit the mobilization of angiogenic<sup> </sup>cells into the circulation, and we block tumor vascularization,"<sup> </sup>said Semenza. "At least in these xenograft models, when you<sup> </sup>block tumor vascularization, you block tumor growth."<sup> </sup>
Master Regulator
In recent years, HIF-1 has emerged as a critical regulator of<sup> </sup>cancer growth, progression, and metastasis. High HIF-1 levels<sup> </sup>in tumor cells have been linked to poor patient outcomes in<sup> </sup>bladder, breast, cervical, endometrial, lung, and pancreatic<sup> </sup>cancers, among others. HIF-1 enables tumor cells to thrive under<sup> </sup>the hypoxic conditions that have been the bane of oncologists<sup> </sup>trying to wipe out cancer cells remaining after radiation and<sup> </sup>chemotherapy.
Mol Carcinog. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Mol%20Carci nog.%27%29;) 2009 Oct 12. [Epub ahead of print]
Aryl hydrocarbon nuclear translocator (hypoxia inducible factor 1beta) activity is required more during early than late tumor growth.
Shi S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Shi%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Yoon DY (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Yoon%20DY%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Hodge-Bell K (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Hodge-Bell%20K%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Huerta-Yepez S (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Huerta-Yepez%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract), Hankinson O (http://www.ncbi.nlm.nih.gov/pubmed?term=%22Hankinson%20O%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVAbstract).
Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California.
c4 is a derivative of the mouse hepatoma cell line, Hepa-1, that harbors a mutation in the aryl hydrocarbon receptor nuclear translocator gene (Arnt, or hypoxia inducible factor 1beta [HIF-1beta]) leading to loss of activity. Clone 3 cells were generated by introducing a doxycycline-repressible Arnt expression vector into c4 cells. Clone 3 cells were injected subcutaneously into immunosuppressed mice, which were treated with doxycyline (a) throughout the growth of the subsequent tumor xenografts, or (b) from day 7 through to the end of the experiment (day 30), or not treated (c). Tumors in all groups grew exponentially between days 14 and 30, and at rates that were indistinguishable from each other. However, tumors in group a were smaller than those of the other two groups throughout the measurable growth period, while tumor volumes in groups b and c were not significantly different from each other. The degrees of vascularity and apoptosis did not correlate with the differences in degrees of growth between the different groups. Thus, Arnt is required during the early stages of growth of the tumors but less in later stages. Since Arnt does not detectably effect the growth kinetics of Hepa-1 cells either during hypoxia or normoxia, this requirement is unlikely to reflect a direct effect of Arnt on cell proliferation, and is therefore probably a consequence of altered interaction(s) between the tumor cells and the host. These studies suggest that Arnt (and HIF-1alpha/HIF-2alpha) inhibitors will be particularly effective against smaller tumors, including micrometastases. (c) 2009 Wiley-Liss, Inc.
PMID: 19824022 [PubMed - as supplied by publisher]