Abstract LB-35: Site specific activation of AKT protects cells from death induced by glucose deprivation .

Abstract

Abstract The serine/threonine kinase AKT is a key mediator of cancer cell survival. We demonstrate that transient glucose deprivation modestly induces AKT phosphorylation at both Thr308 and Ser473. In contrast, prolonged glucose deprivation induces selective AKT phosphorylation at Thr308 and phosphorylation of a distinct subset of AKT downstream targets leading to cell survival under metabolic stress. Glucose deprivation-induced AKT Thr308 phosphorylation is dependent on PDK1 and PI3K but not EGFR or IGF1R. Prolonged glucose-deprivation induces the formation of a complex of AKT, PDK1, and the GRP78 chaperone protein, directing phosphorylation of AKT at Thr308 but not Ser473. Our results reveal a novel mechanism of AKT activation under prolonged metabolic stress that protects cells from metabolic stress. The selective activation of AKT phosphorylation at Thr308 that occurs during prolonged nutrient deprivation may provide an unexpected opportunity for the development and implementation of drugs targeting cell metabolism and aberrant AKT signaling. Citation Format: Meng Gao, Jiyong Liang, Yiling Lu, Huifang Guo, Peter German, Shanshan Bai, Eric Jonasch, Xingsheng Yang, Gordon B. Mills, Zhiyong Ding. Site specific activation of AKT protects cells from death induced by glucose deprivation . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-35. doi:10.1158/1538-7445.AM2013-LB-35