Maintenance Of Aerobic Glycolysis Provides Selective Protection From Apoptosis Upon Loss Of Growth Signals Or Inhibition Of Bcr-Abl Through Suppression Of P53 Activation

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Healthy cells require input from growth factor signaling pathways to maintain cell metabolism and survival. In contrast, cancer cells can maintain growth factor-independent glycolysis and survival through expression of oncogenic kinases, such as BCR-Abl. While disruption of these growth signals through targeted kinase inhibition can promote cancer cell death, therapeutic resistance frequently develops, and further mechanistic understanding is needed. Cell metabolism may play a central role in this cell death pathway, as we have shown that growth factor deprivation leads to decreased glycolysis that promotes apoptosis via p53 activation and induction of the pro-apoptotic protein Puma. However, it has remained unclear how cell metabolism regulates p53 activation. To investigate this, we have utilized a system in which stable overexpression of the glucose transporter Glut1 and hexokinase 1 in hematopoietic cells drives growth factor-independent glycolysis. This system allows us to examine the effects of altered glucose metabolism in the absence of other signaling events activated downstream of growth factor receptors or oncogenic kinases. Here, we extend our findings to demonstrate that elevated glucose metabolism, characteristic of cancer cells, can suppress Protein Kinase C delta-dependent p53 activation to maintain cell survival after growth factor withdrawal. In contrast, DNA damage-induced p53 activation was independent of Protein Kinase C delta and was not metabolically sensitive. Both stresses required phosphorylation of p53 at serine 18 for maximal activity, but each led to a unique pattern of p53 target gene expression, demonstrating distinct activation and response pathways for p53 that were differentially regulated by metabolism. Consistent with oncogenic kinases acting to replace growth factors, treatment of BCR-Abl-expressing cells with the kinase inhibitor imatinib led to reduced glycolysis and p53- and Puma-dependent cell death. Accordingly, maintenance of glucose metabolism inhibited p53 activation and promoted imatinib resistance. Furthermore, inhibition of glycolysis enhanced imatinib sensitivity in BCR-Abl-positive cells expressing wild type p53 but had little effect on p53-null cells. These data demonstrate that distinct pathways regulate p53 after DNA damage and metabolic stress and that inhibition of glucose metabolism may enhance the efficacy of and overcome resistance to targeted molecular cancer therapies. 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 LB-261. doi:10.1158/1538-7445.AM2011-LB-261