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Rich66 · 11-08-2009, 03:59 AM

http://www.nature.com/nature/journal...ture06734.html

Nature 452, 230-233 (13 March 2008) | doi:10.1038/nature06734; Received 18 October 2007; Accepted 19 January 2008
The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth

Heather R. Christofk¹, Matthew G. Vander Heiden^1,², Marian H. Harris³, Arvind Ramanathan⁴, Robert E. Gerszten^4,^5,⁶, Ru Wei⁴, Mark D. Fleming³, Stuart L. Schreiber^4,⁷ & Lewis C. Cantley^1,⁸

Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA
Department of Pathology, Children's Hospital, Boston, Massachusetts 02115, USA
Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
Cardiology Division and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, Massachusetts 02129, USA
Donald W. Reynolds Cardiovascular Clinical Research Center on Atherosclerosis, Harvard Medical School, Boston, Massachusetts 02115, USA
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA

Correspondence to: Lewis C. Cantley^1,⁸ Correspondence and requests for materials should be addressed to L.C.C. (Email: lcantley@hms.harvard.edu).

Many tumour cells have elevated rates of glucose uptake but reduced rates of oxidative phosphorylation. This persistence of high lactate production by tumours in the presence of oxygen, known as aerobic glycolysis, was first noted by Otto Warburg more than 75 yr ago¹. How tumour cells establish this altered metabolic phenotype and whether it is essential for tumorigenesis is as yet unknown. Here we show that a single switch in a splice isoform of the glycolytic enzyme pyruvate kinase is necessary for the shift in cellular metabolism to aerobic glycolysis and that this promotes tumorigenesis. Tumour cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase². Here we use short hairpin RNA to knockdown pyruvate kinase M2 expression in human cancer cell lines and replace it with pyruvate kinase M1. Switching pyruvate kinase expression to the M1 (adult) isoform leads to reversal of the Warburg effect, as judged by reduced lactate production and increased oxygen consumption, and this correlates with a reduced ability to form tumours in nude mouse xenografts. These results demonstrate that M2 expression is necessary for aerobic glycolysis and that this metabolic phenotype provides a selective growth advantage for tumour cells in vivo.

Oncogene. 2006 Aug 7;25(34):4777-86.
Hexokinase II: cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria.

Mathupala SP, Ko YH, Pedersen PL.
Department of Neurological Surgery and Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
A key hallmark of many cancers, particularly the most aggressive, is the capacity to metabolize glucose at an elevated rate, a phenotype detected clinically using positron emission tomography (PET). This phenotype provides cancer cells, including those that participate in metastasis, a distinct competitive edge over normal cells. Specifically, after rapid entry of glucose into cancer cells on the glucose transporter, the highly glycolytic phenotype is supported by hexokinase (primarily HK II) that is overexpressed and bound to the outer mitochondrial membrane via the porin-like protein voltage-dependent anion channel (VDAC). This protein and the adenine nucleotide transporter move ATP, newly synthesized by the inner membrane located ATP synthase, to active sites on HK II. The abundant amounts of HK II bind both the ATP and the incoming glucose producing the product glucose-6-phosphate, also at an elevated rate. This critical metabolite then serves both as a biosynthetic precursor to support cell proliferation and as a precursor for lactic acid, the latter exiting cancer cells causing an unfavorable environment for normal cells. Although helping facilitate this chemical warfare, HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host. For these reasons, targeting this key enzyme is currently being investigated in several laboratories in a strategy to develop novel therapies that may turn the tide on the continuing struggle to find effective cures for cancer. One such candidate is 3-bromopyruvate that has been shown recently to eradicate advanced stage, PET positive hepatocellular carcinomas in an animal model without apparent harm to the animals.

PMID: 16892090 [PubMed - indexed for MEDLINE]

Cancers' sweet tooth may be weakness

http://www.physorg.com/news177769436.html
November 18th, 2009 in Medicine & Health / Cancer
The pedal-to-the-metal signals driving the growth of several types of cancer cells lead to a common switch governing the use of glucose, researchers at Winship Cancer Institute of Emory University have discovered.
Scientists who study cancer have known for decades that cancer cells tend to consume more glucose, or blood sugar, than healthy cells. This tendency is known as the "Warburg effect," honoring discoverer Otto Warburg, a German biochemist who won the 1931 Nobel Prize in Medicine. Now a Winship-led team has identified a way to possibly exploit cancer cells' taste for glucose.
The results were published this week in the journal Science Signaling.
Normally cells have two modes of burning glucose, comparable to sprinting and long-distance running: glycolysis, which doesn't require oxygen and doesn't consume all of the glucose molecule, and oxidative phosphorylation, which requires oxygen and is more thorough.
Cancer cells often outgrow their blood supply, leading to a lack of oxygen in a tumor, says Jing Chen, PhD, assistant professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute. They also benefit from glycolysis because leftovers from the inefficient consumption of glucose can be used as building blocks for growing cells.
"Even if they have oxygen, cancer cells still prefer glycolysis," Chen says. "They depend on it to grow quickly."
Working with Chen, postdoctoral researcher Taro Hitosugi focused on the enzyme PKM2 (pyruvate kinase M2), which governs the use of glucose and controls whether cells make the switch between glycolysis and oxidative phosphorylation. PKM2 is found predominantly in fetal cells and in tumor cells.
In many types of cancer, mutations lead to over-activation of proteins called tyrosine kinases. Chen's team showed that tyrosine kinases turn off PKM2 in lung, breast, prostate and blood cancers. Introducing a form of PKM2 that is not sensitive to tyrosine kinases into cancer cells forces them to grow slower and be more dependent on oxygen, they found.
Because the active form of PKM2 consists of four protein molecules stuck together, having a tyrosine kinase flip the "off" switch on one molecule can dampen the activity for the others.
"People knew that tyrosine kinases might modify PKM2 for decades but they didn't think it mattered," Chen says. "We showed that such a modification is important and you even don't need that much modification of PKM2 to make a difference in the cells' metabolism."
PKM2 could be a good drug target, because both inhibiting it or activating it can slow down cancer cell growth. Biotechnology companies are already searching for ways to do so, Chen says.
More information: T. Hitosugi et al. Tyrosine phosphorylation inhibits PKM2 to promote the Wargurg effect and tumor growth. Sci. Signal. 2, ra73 (2009).
Source: Emory University (news : web) http://www.physorg.com/news177769436.html

11-08-2009, 03:59 AM	#5
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: 3-bromopyruvate http://www.nature.com/nature/journal...ture06734.html Nature 452, 230-233 (13 March 2008) \| doi:10.1038/nature06734; Received 18 October 2007; Accepted 19 January 2008 The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth Heather R. Christofk¹, Matthew G. Vander Heiden^1,², Marian H. Harris³, Arvind Ramanathan⁴, Robert E. Gerszten^4,^5,⁶, Ru Wei⁴, Mark D. Fleming³, Stuart L. Schreiber^4,⁷ & Lewis C. Cantley^1,⁸ Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA Department of Pathology, Children's Hospital, Boston, Massachusetts 02115, USA Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA Cardiology Division and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, Massachusetts 02129, USA Donald W. Reynolds Cardiovascular Clinical Research Center on Atherosclerosis, Harvard Medical School, Boston, Massachusetts 02115, USA Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA Correspondence to: Lewis C. Cantley^1,⁸ Correspondence and requests for materials should be addressed to L.C.C. (Email: lcantley@hms.harvard.edu). Many tumour cells have elevated rates of glucose uptake but reduced rates of oxidative phosphorylation. This persistence of high lactate production by tumours in the presence of oxygen, known as aerobic glycolysis, was first noted by Otto Warburg more than 75 yr ago¹. How tumour cells establish this altered metabolic phenotype and whether it is essential for tumorigenesis is as yet unknown. Here we show that a single switch in a splice isoform of the glycolytic enzyme pyruvate kinase is necessary for the shift in cellular metabolism to aerobic glycolysis and that this promotes tumorigenesis. Tumour cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase². Here we use short hairpin RNA to knockdown pyruvate kinase M2 expression in human cancer cell lines and replace it with pyruvate kinase M1. Switching pyruvate kinase expression to the M1 (adult) isoform leads to reversal of the Warburg effect, as judged by reduced lactate production and increased oxygen consumption, and this correlates with a reduced ability to form tumours in nude mouse xenografts. These results demonstrate that M2 expression is necessary for aerobic glycolysis and that this metabolic phenotype provides a selective growth advantage for tumour cells in vivo. Oncogene. 2006 Aug 7;25(34):4777-86. Hexokinase II: cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Mathupala SP, Ko YH, Pedersen PL. Department of Neurological Surgery and Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA. A key hallmark of many cancers, particularly the most aggressive, is the capacity to metabolize glucose at an elevated rate, a phenotype detected clinically using positron emission tomography (PET). This phenotype provides cancer cells, including those that participate in metastasis, a distinct competitive edge over normal cells. Specifically, after rapid entry of glucose into cancer cells on the glucose transporter, the highly glycolytic phenotype is supported by hexokinase (primarily HK II) that is overexpressed and bound to the outer mitochondrial membrane via the porin-like protein voltage-dependent anion channel (VDAC). This protein and the adenine nucleotide transporter move ATP, newly synthesized by the inner membrane located ATP synthase, to active sites on HK II. The abundant amounts of HK II bind both the ATP and the incoming glucose producing the product glucose-6-phosphate, also at an elevated rate. This critical metabolite then serves both as a biosynthetic precursor to support cell proliferation and as a precursor for lactic acid, the latter exiting cancer cells causing an unfavorable environment for normal cells. Although helping facilitate this chemical warfare, HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host. For these reasons, targeting this key enzyme is currently being investigated in several laboratories in a strategy to develop novel therapies that may turn the tide on the continuing struggle to find effective cures for cancer. One such candidate is 3-bromopyruvate that has been shown recently to eradicate advanced stage, PET positive hepatocellular carcinomas in an animal model without apparent harm to the animals. PMID: 16892090 [PubMed - indexed for MEDLINE] Cancers' sweet tooth may be weakness http://www.physorg.com/news177769436.html November 18th, 2009 in Medicine & Health / Cancer The pedal-to-the-metal signals driving the growth of several types of cancer cells lead to a common switch governing the use of glucose, researchers at Winship Cancer Institute of Emory University have discovered. Scientists who study cancer have known for decades that cancer cells tend to consume more glucose, or blood sugar, than healthy cells. This tendency is known as the "Warburg effect," honoring discoverer Otto Warburg, a German biochemist who won the 1931 Nobel Prize in Medicine. Now a Winship-led team has identified a way to possibly exploit cancer cells' taste for glucose. The results were published this week in the journal Science Signaling. Normally cells have two modes of burning glucose, comparable to sprinting and long-distance running: glycolysis, which doesn't require oxygen and doesn't consume all of the glucose molecule, and oxidative phosphorylation, which requires oxygen and is more thorough. Cancer cells often outgrow their blood supply, leading to a lack of oxygen in a tumor, says Jing Chen, PhD, assistant professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute. They also benefit from glycolysis because leftovers from the inefficient consumption of glucose can be used as building blocks for growing cells. "Even if they have oxygen, cancer cells still prefer glycolysis," Chen says. "They depend on it to grow quickly." Working with Chen, postdoctoral researcher Taro Hitosugi focused on the enzyme PKM2 (pyruvate kinase M2), which governs the use of glucose and controls whether cells make the switch between glycolysis and oxidative phosphorylation. PKM2 is found predominantly in fetal cells and in tumor cells. In many types of cancer, mutations lead to over-activation of proteins called tyrosine kinases. Chen's team showed that tyrosine kinases turn off PKM2 in lung, breast, prostate and blood cancers. Introducing a form of PKM2 that is not sensitive to tyrosine kinases into cancer cells forces them to grow slower and be more dependent on oxygen, they found. Because the active form of PKM2 consists of four protein molecules stuck together, having a tyrosine kinase flip the "off" switch on one molecule can dampen the activity for the others. "People knew that tyrosine kinases might modify PKM2 for decades but they didn't think it mattered," Chen says. "We showed that such a modification is important and you even don't need that much modification of PKM2 to make a difference in the cells' metabolism." PKM2 could be a good drug target, because both inhibiting it or activating it can slow down cancer cell growth. Biotechnology companies are already searching for ways to do so, Chen says. More information: T. Hitosugi et al. Tyrosine phosphorylation inhibits PKM2 to promote the Wargurg effect and tumor growth. Sci. Signal. 2, ra73 (2009). Source: Emory University (news : web) http://www.physorg.com/news177769436.html