Abstract 1266: Oncogenic stress induced by Bcr-Abl over-activation leads to cell death mediated by a massively enhanced aerobic glycolysis

Abstract

Abstract It is well established that normal cells respond to over-activation of oncogenes by induction of genetically encoded programs such as apoptosis or senescence. Therefore, too much activity of a growth promoting oncogene seems to disturb the cellular homeostasis, a phenomenon which is known as oncogenic stress. To investigate the molecular mechanisms behind this phenomenon we used cell clones overexpressing the oncogene Bcr-Abl and cultivated them continuously in the presence of the Bcr-Abl inhibitor Imatinib. Removal of Imatinib led to a robust induction of Bcr-Abl autophosphorylation and concomitant overstimulation of the Bcr-Abl downstream pathways PI3K/AKT-, RAS/MAPK-, and JAK/STAT. Importantly, this acute over-activation of Bcr-Abl resulted in a delayed non-apoptotic cell death starting not before 48 hours after Imatinib withdrawal. This cell death was preceded by a massively enhanced aerobic glycolysis and glutaminolysis (Warburg effect) and amino acid metabolism leading to an elevated cellular ATP and protein content. During the first 30 hours after Imatinib deprivation the enhanced metabolism had no effect on proliferation but resulted in cellular swelling, cytoplasmic vacuolization, and massive induction of ER stress markers indicating that Bcr-Abl over-activation induces ER stress response. However, cell death upon Bcr-Abl over-activation was not dependent on this severe ER stress since siRNA mediated knockdown of CHOP and BIM had no effect on cell viability. In contrast, both inhibition of aerobic glycolysis by 2-deoxy-glucose as well as reduction of glutamine concentration in the medium were sufficient to block Imatinib deprivation induced cell death. These data demonstrate that the Bcr-Abl over-activation mediated enhanced metabolism is responsible for oncogenic stress induced cell death. Interestingly, screening of 1200 marketed small molecule inhibitors (Prestwick chemical library) for their potential effects on oncogenic stress response uncovered selectively steroids to effectively antagonize both ER stress and cell death upon Bcr-Abl over-activation. These agents were also able to normalize cellular metabolism upon Imatinib withdrawal, supporting the view that “overshooting” metabolism upon oncogenic over-activation leads to cell death. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1266. doi:10.1158/1538-7445.AM2011-1266