Metabolic Plasiticy in Cancers-Distinct Role of Glycolytic Enzymes GPI, LDHs or Membrane Transporters MCTs

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.

Keywords: CRISPR-Cas9; cancer; glycolysis; immune response; lactic acid; metabolism; oxidative phosphorylation; pentose phosphate pathway.

Figure 1

Glucose and glutamine catabolism provide tumor cells with biosynthetic precursors. Glucose transport and glycolytic flux are accelerated in cancer cells, when compared to normal cells, due to increased expression of appropriate transporters and enzyme isoforms. Glucose-6-phosphate dehydrogenase (G6PDH) shunts G6P from the glycolysis into the oxidative branch of pentose phosphate pathway (PPP). Intermediates from glycolysis and TCA cycle replenish biosynthetic pathways to produce macromolecules (nucleic acids, lipids, and proteins) necessary for cell proliferation. Only those transporters and enzymes relevant to the text are shown: GLUT1, glucose-6-phosphate isomerase, lactate dehydrogenase A (LDHA)/-B, MCT1/4. HIF- targets are in red and CRISPR-Cas9 targets studied in our lab are identified with red arrows.

Figure 2

Metabolic reprogramming in glucose-6-phosphate isomerase (GPI)-KO cells. A switch from glycolytic metabolism to oxidative phosphorylation (OXPHOS) caused by the complete GPI disruption is shown. LS174T WT cells are highly glycolytic and do not use mitochondria for ATP production (A). Contrarily, cells survive GPI disruption by re-activating pentose phosphate pathway (PPP) and OXPHOS (B). Oxygen consumption rate (OCR) of LS174T WT and GPI-KO cells was evaluated with Seahorse XF24 bioanalyzer (C). The mean ± SEM is representative of four independent experiments performed in quadruplicate. The figure is adapted from Ref. (39). Glc, glucose, oligo, oligomycin, FCCP, carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone, rot, rotenone, antA, antimycin A.