Metabolic plasiticy in cancers-distinct role of glycolytic enzymes GPI, LDHs or membrane transporters MCTs

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Abstract

Research on cancer metabolism has recently re-surfaced as a major focal point in cancer field with a reprogrammed metabolism no longer being considered as a mere consequence of oncogenic transformation, but as a hallmark of cancer. Reprogramming metabolic pathways and nutrient sensing is an elaborate way by which cancer cells respond to high bioenergetic and anabolic demands during tumorigenesis. Thus, inhibiting specific metabolic pathways at defined steps should provide potent ways of arresting tumor growth. However, both animal models and clinical observations have revealed that this approach is seriously limited by an extraordinary cellular metabolic plasticity. The classical example of cancer metabolic reprogramming is the preference for aerobic glycolysis, or Warburg effect, where cancers increase their glycolytic flux and produce lactate regardless of the presence of the oxygen. This allows cancer cells to meet the metabolic requirements for high rates of proliferation. Here, we discuss the benefits and limitations of disrupting fermentative glycolysis for impeding tumor growth at three levels of the pathway: (i) an upstream block at the level of the glucose-6-phosphate isomerase (GPI), (ii) a downstream block at the level of lactate dehydrogenases (LDH, isoforms A and B), and (iii) the endpoint block preventing lactic acid export (MCT1/4). Using these examples of genetic disruption targeting glycolysis studied in our lab, we will discuss the responses of different cancer cell lines in terms of metabolic rewiring, growth arrest, and tumor escape and compare it with the broader literature.

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Ždralević, M., Marchiq, I., de Padua, M. M. C., Parks, S. K., & Pouysségur, J. (2017, December 20). Metabolic plasiticy in cancers-distinct role of glycolytic enzymes GPI, LDHs or membrane transporters MCTs. Frontiers in Oncology. Frontiers Media S.A. https://doi.org/10.3389/fonc.2017.00313

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