Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development

Abstract

Glucose is a key metabolite used by cancer cells to generate ATP, maintain redox state and create biomass. Glucose can be catabolized to lactate in the cytoplasm, which is termed glycolysis, or alternatively can be catabolized to carbon dioxide and water in the mitochondria via oxidative phosphorylation. Metabolic heterogeneity exists in a subset of human tumors, with some cells maintaining a glycolytic phenotype while others predominantly utilize oxidative phosphorylation. Cells within tumors interact metabolically with transfer of catabolites from supporting stromal cells to adjacent cancer cells. The Reverse Warburg Effect describes when glycolysis in the cancer-associated stroma metabolically supports adjacent cancer cells. This catabolite transfer, which induces stromal-cancer metabolic coupling, allows cancer cells to generate ATP, increase proliferation, and reduce cell death. Catabolites implicated in metabolic coupling include the monocarboxylates lactate, pyruvate, and ketone bodies. Monocarboxylate transporters (MCT) are critically necessary for release and uptake of these catabolites. MCT4 is involved in the release of monocarboxylates from cells, is regulated by catabolic transcription factors such as hypoxia inducible factor 1 alpha (HIF1A) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and is highly expressed in cancer-associated fibroblasts. Conversely, MCT1 is predominantly involved in the uptake of these catabolites and is highly expressed in a subgroup of cancer cells. MYC and TIGAR, which are genes involved in cellular proliferation and anabolism, are inducers of MCT1. Profiling human tumors on the basis of an altered redox balance and intra-tumoral metabolic interactions may have important biomarker and therapeutic implications. Alterations in the redox state and mitochondrial function of cells can induce metabolic coupling. Hence, there is interest in redox and metabolic modulators as anticancer agents. Also, markers of metabolic coupling have been associated with poor outcomes in numerous human malignancies and may be useful prognostic and predictive biomarkers.

Keywords: TIGAR; caveolin 1; glycolysis; hypoxia inducible factor; lactate; oxidative phosphorylation.

Fig 1. Model of Metabolic Coupling in Cancer

A model of two-compartment tumor metabolism is shown. Cancer cells have high expression of the translocase of outer mitochondrial membrane 20 (TOMM20), monocarboxylate transporter 1 (MCT1) and TP53 induced glycolysis and apoptosis regulator (TIGAR), which induces high oxidative phosphorylation (OXPHOS) and low glycolysis in these cancer cells with high proliferation. This metabolic reprogramming of cancer cells induces oxidative stress, which in turn upregulates monocarboxylate transporter 4 (MCT4) and reduces caveolin 1 (CAV1) expression driving hypoxia inducible factor 1 alpha (HIF1A), nitric oxide (NO), reactive oxygen species (ROS) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) in cancer-associated fibroblasts.

Fig 2. Mechanisms of Metabolic Reprogramming in Cancer

Reactive oxygen species (ROS), hypoxia inducible factor 1 alpha (HIF1A) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) induce glycolysis with lactate production in cancer-associated fibroblasts which in turn downregulates caveolin 1 (CAV1) and upregulates monocarboxylate transporter 4 (MCT4). Lactate is released from fibroblasts and uptaken by cancer cells via monocarboxylate transporter 1 (MCT1) with upregulation of TP53 induced glycolysis and apoptosis regulator (TIGAR). These cancer cells have high mitochondrial oxidative phosphorylation (OXPHOS) and low glycolysis, which is associated with high proliferation, low apoptosis rates, tumor growth and higher rates of relapse and death.