Abstract B03: Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancers

摘要: Abstracts: AACR Special Conference: Metabolism and Cancer; June 7-10, 2015; Bellevue, WA Glutamine addiction is a major metabolic reprogramming event that occurs in cancer cells. Many tumors exhibit oncogene-dependent to glutamine. PIK3CA, which encodes the p110 alpha catalytic subunit of phosphatidylinositol 3-kinase, most frequently mutated oncogene human cancers. However, whether PIK3CA mutations reprogram metabolism an important unaddressed question. Using isogenic cell lines expressing either wild-type (WT) or oncogenic mutant allele we demonstrated colorectal cells harboring are more dependent on glutamine grow. In contrast, WT did not show differential sensitivity glucose deprivation. Through gene expression analyses, showed glutamate pyruvate transaminase 2 (GPT2) up-regulated with compared PIK3CA. We induction GPT2 by necessary sufficient render Moreover, aminooxyacetate, inhibits enzymatic activity aminotransferases including GPT2, suppresses xenograft tumor growth cancers mutations, but Thus our data suggest targeting may be effective approach treat patients mutations. Mutant up-regulates through AKT-independent PDK1-RSK2-ATF4 signaling axis. ATF4 transcription factor activates expression. further RSK2 kinase PDK1. Activated then phosphorylates at serine residue 245, turn recruits deubiquitinase USP8 protects from ubiquitin-mediated degradation. Lastly, using [13C5-]glutamine isotope-tracing technology, convert alpha-keto-glutarate replenish tricarboxylic acid cycle generate ATP. Together, establish as cause cancers. Citation Format: Zhenghe Wang. Oncogenic [abstract]. In: Proceedings Jun WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B03.