Abstract 1265: Survival under glucose and serum deprivation is increased by DN-mutant p53 R175H in human melanoma: A possible gain of oncogenic function

Abstract

Abstract BACKGROUND.- To help counteract tumor development, the p53 tumor suppressor protein functions to preserve genomic stability, when inhibiting cell cycle progression or inducing senescence or apoptosis. However, cancer-associated dominant-negative (DN) p53 mutations can override the tumor suppressor functions of wt p53, through possible gain-of oncogenic functions including those increasing resistance to metabolic stress. OBJECTIVES.- Since hypoglycemia and growth factor shortage may intermittently occur in the microenvironment of poorly vascularized tumors, this report investigated whether metabolic restriction (glucose deprivation and low serum supplementation), unequally influence the survival of genetically-matched human C8161 melanoma harbouring wt or DN-R175H mutant p53.(Strasberg-Rieber, M. et al. Clin. Cancer Res.7(2001)1446). RESULTS.- Cell death by prolonged metabolic restriction increased oxidative stress, since it was counteracted by the anti-oxidant N-acetylcysteine. Melanoma cells harbouring the DN-mutant p53 R175H were more resistant to cell death induced by shorter metabolic restriction. DPI, a NADPH oxidase inhibitor of superoxide generation counteracted the greater resistance of glucose-deprived mutant p53 cells, by altering expression of mitochondrial Mn-SOD∼SOD2. Pyruvate preferentially protected from DPI treatment under metabolic restriction, restoring levels of MnSOD. CONCLUSIONS. our results suggests that tumor cell death in response to anti-glycolytic treatment, may be antagonized by DN-mutant p53R175H. 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 1265. doi:10.1158/1538-7445.AM2011-1265