Addiction to Coupling of the Warburg Effect with Glutamine Catabolism in Cancer Cells

Abstract

SUMMARY Metabolic reprogramming is critical to oncogenesis, but the emergence and function of this profound reorganization remain poorly understood. Here we find that cooperating oncogenic mutations drive large-scale metabolic reprogramming, which is both intrinsic to cancer cells and obligatory for the transition to malignancy. This involves synergistic regulation of several genes encoding metabolic enzymes, including the lactate dehydrogenases LDHA and LDHB and mitochondrial glutamic pyruvate transaminase 2 (GPT2). Notably, GPT2 engages activated glycolysis to drive the utilization of glutamine as a carbon source for TCA cycle anaplerosis in colon cancer cells. Our data indicate that the Warburg effect supports oncogenesis via GPT2-mediated coupling of pyruvate production to glutamine catabolism. Although critical to the cancer phenotype, GPT2 activity is dispensable in cells that are not fully transformed, thus pinpointing a metabolic vulnerability specifically associated with cancer cell progression to malignancy.

Glutamine Metabolism in Cancer: Understanding the Heterogeneity

“…Some breast cancer cells are known to catabolize glutamate primarily via transaminases, thus conserving the amine nitrogen [59]. Alanine transaminase 2 (GPT2), in particular, is critical for α-KG generation and therefore for glutamine/glutamate-mediated TCA cycle anaplerosis in colon cancer cells [60, 61]. In contrast to proliferative cells, transaminase expression is low in quiescent cells, and instead GLUD expression is induced [62].…”

Targeting amino acid metabolism for cancer therapy

“…Consistent with these findings, highly proliferative human breast tumors display high transaminase and low GLUD expression, with expression of the transaminase genes PSAT1 (cytosolic serine synthesis), GPT2 (mitochondrial alanine synthesis) and GOT1 (cytosolic aspartate synthesis) correlating strongly with proliferation rate [36]. Oncogenic KRAS suppresses GLUD and upregulates GOT1 expression in pancreatic ductal adenocarcinoma as part of a metabolic program that supports redox homeostasis [12], and GPT2 is overexpressed in colon tumors, driving glutamine utilization for TCA cycle anaplerosis [37,38]. However, GLUD has important roles in certain tumors, and knockdown of GLUD1 expression in lung cancer cells inhibits tumorigenesis in a xenograft model [39].…”

Metabolic switching and cell fate decisions: implications for pluripotency, reprogramming and development

“…This is seen in muscle cells, under anaerobic conditions when the electron transport chain is inactive [2] This mode of metabolism is frequently seen in tumor cells under aerobic conditions and generally referred to as the ‘Warburg effect’ or, ‘aerobic glycolysis’ [3]. Glutamine-dependent energy generation involves its conversion to α-ketoglutarate, which then feeds into the TCA cycle to drive energy generation [4,5]. …”