Abstract 1059: Pancreatic cancer cells acclimatize to low pH by increasing glutamine metabolism

Abstract

Abstract Pancreatic cancer (PC) is the fourth leading cause of cancer related deaths in the United States. PC has a five-year survival rate of only 6%; this is due to the lack of specific symptoms at the earliest stages of disease progression. Currently, surgery is the only treatment option with a reasonable hope of cure; however, due to late detection of the disease, only 15-25% of patients are eligible for surgery. Pancreatic tumors are characterized by increased glucose uptake, high glycolysis rate, and reduced flux to the TCA cycle. This metabolic phenotype, also known as the Warburg effect, is typical of rapidly dividing tumor cells and forms the basis of imaging by utilizing [18F]-FDG-PET (glucose analog). The consequence of this metabolic behavior is the continuous acidification of the tumor microenvironment. Acidification of the tumor microenvironment (TME) and its effects in cancer cell metabolism are not well defined. In this study we analyzed metabolic adaptations of PC cells experiencing physiological pH 7.4 versus cells cultured in 6.8∼7.0 pH that is similar to the pH range observed in the pancreatic TME. Using high performance liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) analysis to determine the metabolite levels of PC cells cultured in these TME conditions, we observed a marked reduction in glycolysis metabolites in cells cultured at low pH. We observed reduced glucose uptake, as well as, reduced lactate secretion in low pH culture conditions. Furthermore, we observed that cells in low pH microenvironment were able to survive upon glucose deprivation, but not upon glutamine deprivation. In contrast, cells in normal physiologic pH culture could not survive upon glucose deprivation. Based on the up regulation of metabolites in the glutaminolysis pathway identified through LC/MS/MS analysis, and the increase in metabolic enzyme mRNA levels, as well as the increased sensitivity to inhibitors of this pathway, we conclude that glutamine metabolism is essential for survival of pancreatic cancer cells under low pH conditions. Furthermore, due to the increased levels of ATP and sensitivity of low-pH cultured cells to oligomycin, we conclude that oxidative phosphorylation is essential for the maintenance of cellular homeostasis at low pH. Such changes result in reduced Warburg Effect, denoted by reduced lactate release. This is the first study to establish glutamine dependence of PC cells under low pH conditions. Our results may provide novel therapeutic opportunities for targeting metabolic adaptations in pancreatic cancer cells in response to changes in the microenvironment. Citation Format: Jaime Abrego, Venugopal Gunda, Pankaj K. Singh, Gennifer Goode. Pancreatic cancer cells acclimatize to low pH by increasing glutamine metabolism. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1059.