Cell Cycle. 2011 Aug 1;10(15):2521-8. Epub 2011 Aug 1.
Understanding the metabolic basis of drug resistance: therapeutic induction of the Warburg effect kills cancer cells.
Martinez-Outschoorn UE,
Lin Z,
Ko YH,
Goldberg AF,
Flomenberg N,
Wang C,
Pavlides S,
Pestell RG,
Howell A,
Sotgia F,
Lisanti MP.
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The Jefferson Stem Cell Biology and Regenerative Medicine Center, Kimmel Cancer Center; Thomas Jefferson University, Philadelphia, PA, USA.
Abstract
Previously, we identified a form of epithelial-stromal metabolic coupling, in which cancer cells induce aerobic glycolysis in adjacent stromal fibroblasts, via oxidative stress, driving autophagy and mitophagy. In turn, these cancer-associated fibroblasts provide recycled nutrients to epithelial cancer cells, "fueling" oxidative mitochondrial metabolism and anabolic growth. An additional consequence is that these glycolytic fibroblasts protect cancer cells against apoptosis, by providing a steady nutrient stream of to mitochondria in cancer cells. Here, we investigated whether these interactions might be the basis of tamoxifen-resistance in ER(+) breast cancer cells. We show that MCF7 cells alone are Tamoxifen-sensitive, but become resistant when co-cultured with hTERT-immortalized human fibroblasts. Next, we searched for
a drug combination (Tamoxifen + Dasatinib) that could over-come fibroblast-induced Tamoxifen-resistance. Importantly, we show that this drug combination acutely induces the Warburg effect (aerobic glycolysis) in MCF7 cancer cells, abruptly cutting off their ability to use their fuel supply, effectively killing these cancer cells. Thus, we believe that the Warburg effect in tumor cells is not the "root cause" of cancer, but rather it may provide the necessary clues to preventing chemo-resistance in cancer cells. Finally, we observed that
this drug combination (Tamoxifen + Dasatinib) also had a generalized anti-oxidant effect, on both co-cultured fibroblasts and cancer cells alike, potentially reducing tumor-stroma co-evolution. Our results are consistent with the idea that chemo-resistance may be both a metabolic and stromal phenomenon that can be overcome by targeting mitochondrial function in epithelial cancer cells. Thus,
simultaneously targeting both (1) the tumor stroma and (2) the epithelial cancer cells, with combination therapies, may be the most successful approach to anti-cancer therapy. This general strategy of combination therapy for overcoming drug resistance could be applicable to many different types of cancer.
- PMID:
- 21768775
- [PubMed - in process]
- PMCID: PMC3180190
- [Available on 2012/8/1]
Dasatinib (Brand name: Sprycel)
Public release date: 6-Nov-2011
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Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center Metabolic protein plays unexpected role in tumor cell formation and growth
http://www.eurekalert.org/pub_releas...-mpp110411.php
One enzyme controls both cancer cell metabolism and cell cycle progression
In metabolism, PKM2 enhances oxygen-driven processing of sugar known as aerobic glycolysis or the Warburg effect found in tumor cells.
"Cancer cell metabolism and cancer cell cycle progression, which are essential for tumor formation, are conventionally thought to be regulated primarily by distinct signaling complexes," Lu said. The
new findings integrate the two major mechanisms for regulating cancer cell growth by a key metabolic enzyme. "These two important regulatory processes are under the control of pyruvate kinase M2."
New insight into brain malignancies and cancer therapy
Beta-catenin activation that is independent of the Wnt signaling pathway have been observed in many types of cancer. This study reveals a critical mechanism underlying Wnt-independent beta-catenin activation and indicates that c-Src-phosphorylated beta-catenin and nuclear PKM2 are independent predictors of glioma malignancy.
The researchers analyzed brain tumors in 84 patients who had been treated with radiation and chemotherapy after surgery. Those who had low beta-catenin Y333 phosphorylation or low expression of PKM2 in the nucleus (28 cases each) had a median survival of 185 weeks and 130 weeks, respectively.
Median survival decreased for those who had high levels of beta-catenin phosphorylation or nuclear PKM2 expression (56 cases each) to 69.4 weeks and 82.5 weeks, respectively.
Findings include:
- PKM2-dependent beta-catenin activation is instrumental in EGFR-promoted tumor cell proliferation and brain tumor development.
- c-Src activity, beta-catenin Y333 phosphorylation, and PKM2 nuclear accumulation are positively correlated in human glioblastoma specimens.
- Levels of beta-catenin phosphorylation and nuclear PKM2 are correlated with grades of glioma malignancy and prognosis.
Personalized therapy with Src inhibitors
One potential implication of their research is the potential use of c-Src-dependent beta-catenin Y333 phosphorylation levels as a biomarker for selecting patients for treatment.
"This finding is very important because EGFR-based therapy is not very efficient due to drug resistance, and cancer patients need alternative treatment strategies," Lu said. "Thus, this discovery can potentially serve as a guideline for personalized cancer therapy in the treatment of glioma and other tumors with Src inhibitors."
Src inhibitors include dasatinib, which has been approved by the FDA for leukemia treatment, or bosutinib and saracatinib, which are in clinical trials.
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