Abstract 1133: Glucose deprivation-induced intracellular reactive oxygen species activates the PI3K-AKT axis

Abstract

Abstract Glucose is the most efficient energy source and various cancer cells depend on glycolysis for their energy production. On the other hand, tumor microenvironment is often characterized by nutrient deprived conditions. Glucose concentration of cancer tissues was much lower than that of adjacent non-cancerous tissues in colorectal cancers and other solid tumors. To maintain the survival and proliferation of cancer cells, glucose sensing and adaptation to lean nutritional circumstance must be well organized. Glucose sensing machinery has been studied in yeast system. Snf3, which shares sequence similarity with glucose transporters, and other plasma membrane proteins of S. cerevisiae are able to sense the present of glucose. However, the molecular mechanism of glucose sensing in mammalian cells remains to be elucidated. We have reported that pancreatic cancer cells showed tolerance to glucose deprivation. In these cells, glucose deprivation rapidly induced AKT phosphorylation through PI3K activity. In addition, suppressed AKT expression reduced survival of pancreatic cancer-derived PANC-1 cells under nutrient deprived condition. We assumed that regulation of AKT is relevant to glucose sensing and we further investigated the underlying mechanisms. Glucose analogue 2-deoxyglucose (2-DG) is transported into cells and recognized by the yeast glucose sensing system whereas 2-DG is not phosphorylated by hexokinases in glycolytic system. 2-DG treatment, as well as glucose deprivation, led AKT phosphorylation in PANC-1 cells. Hence, glucose transport may not be involved in the sensing for the AKT phosphorylation but downstream metabolic events may play roles in this phenomenon. Variety of metabolic stresses reportedly induced reactive oxygen species. Glucose deprivation induced slight but significant intracellular hydrogen peroxide (H2O2) level in PANC-1 cells. An anti-oxidant reagent N-acetyl cysteine (NAC) reduced both glucose deprivation-induced H2O2 increase and AKT phosphorylation. Furthermore, low dose extracellular H2O2 treatment increased AKT phosphorylation and this effect was suppressed by PI3K inhibitor LY294002. These results strongly suggest that glucose deprivation-induced H2O2 mediated AKT phosphorylation. Src is involved in an alternative PI3K activating pathway, and Ossa, a scaffold protein as known as FAM120A, specifically activates Src-PI3K pathway under oxidative stress. Glucose deprivation-induced AKT phosphorylation was suppressed by a Src inhibitor PP2. Furthermore, reduction of Ossa expression specifically blocked the glucose deprivation-induced AKT phosphorylation in PANC-1 cells. Taken together, increased intracellular H2O2 evokes PI3K-AKT axis under glucose deprived condition and pivotal roles of Src and Ossa is clarified. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1133. doi:1538-7445.AM2012-1133