GOT1-mediated anaplerotic glutamine metabolism regulates chronic acidosis stress in pancreatic cancer cells

Abstract

The increased rate of glycolysis and reduced oxidative metabolism are the principal biochemical phenotypes observed in pancreatic ductal adenocarcinoma (PDAC) that lead to the development of an acidic tumor microenvironment. The pH of most epithelial cell-derived tumors is reported to be lower than that of plasma. However, little is known regarding the physiology and metabolism of cancer cells enduring chronic acidosis. Here, we cultured PDAC cells in chronic acidosis (pH 6.9~7.0) and observed that cells cultured in low pH had reduced clonogenic capacity. However, our physiological and metabolomics analysis showed that cells in low pH deviate from glycolytic metabolism and rely more on oxidative metabolism. The increased expression of the transaminase enzyme GOT1 fuels oxidative metabolism of cells cultured in low pH by enhancing the non-canonical glutamine metabolic pathway. Survival in low pH is reduced upon depletion of GOT1 due to increased intracellular ROS levels. Thus, GOT1 plays an important role in energy metabolism and ROS balance in chronic acidosis stress. Our studies suggest that targeting anaplerotic glutamine metabolism may serve as an important therapeutic target in PDAC.

Integrated RNA and metabolite profiling of urine liquid biopsies for prostate cancer biomarker discovery

“…It would be interesting to establish if GOT1 knocked-down PC3 and LNCaP cells are more sensitive to ROS-inducing treatments such as ionizing radiation. In PDAC, GOT1 plays a role in anaplerotic metabolism countering ROS production in low pH conditions 53 . However, this is unlikely to be the case in PCa.…”

The plasticity of pancreatic cancer metabolism in tumor progression and therapeutic resistance

“…The end result is increased reducing potential of the cell in the form of NADPH [66]. In a related manner, it has been recently reported that cell survival in the acidic TME imparted by lactate production from elevated glycolysis relies on increased expression of GOT1 and the aforementioned non-canonical glutamine pathway [67]. Considering that KRAS shunts glucose carbon from glycolysis away from the oxidative, NADPH generating branch of the PPP, the GOT2-GOT1-ME1 pathway becomes a major source of cytosolic NADPH production.…”

De Novo Lipid Synthesis Facilitates Gemcitabine Resistance through Endoplasmic Reticulum Stress in Pancreatic Cancer

“…Cancer cells exhibit metabolic properties distinct from normal cells in order to adapt to the nutritional needs for the proliferation (7–9). Cancer cells are more dependent on aerobic glycolysis, fatty acid synthesis, nucleic acid synthesis, and glutamine metabolism (7, 10–12). However, the therapeutic efficacy of targeting the metabolic enzymes in improving the therapeutic resistance and the mechanism by which enzymatic inhibition can overcome the therapeutic resistance is not fully understood.…”