Abstract 2961: The level of mitochondrial apoptotic priming determines cell fate upon p53 restoration

Abstract

Abstract Using genetically engineered mouse models of cancer, we and others have recently shown that a variety of established tumors require sustained inactivation of the p53 pathway. Reactivation of p53 in established tumors typically results in one of two cell fate decisions: cell cycle arrest or cell death via apoptosis. Since p53 is a transcription factor, one hypothesis that may explain these tumor-specific outcomes is that p53 transcriptionally activates a particular set of genes that is specific to each tumor type, in addition to genes involved in a core p53 pathway. Another possibility is that the level of mitochondrial apoptotic priming in a cell might dictate whether p53 activation promotes cell death or cell cycle arrest. To test this, we derived murine p53-restorable cell lines from three different tumor types: lung adenocarcinoma, sarcoma and lymphoma. Upon restoration of the endogenous Trp53 gene, these cell lines undergo cell cycle arrest (lung and sarcoma) or apoptosis (lymphoma). We hypothesized that this tumor-specific response to p53 restoration could be explained by the level of mitochondrial priming on each specific tumor type, where lymphoma cell lines would be highly primed relative to the lung and sarcoma cell lines. Indeed mitochondrial BH3 profiling demonstrated that lymphoma cell lines were highly primed and this correlated with their apoptotic response to p53 restoration. On the other hand, lung and sarcoma cell lines were poorly primed and this was consistent with their cell cycle arrest phenotype upon p53 restoration. Modulating the expression levels of Bcl2 family members to modulate mitochondrial apoptotic priming was sufficient to change the fate of these cells. Lymphoma cell lines were forced to undergo cell cycle arrest upon p53 restoration by overexpression of the anti-apoptotic Bcl2 family members Bcl-2 or Bcl-XL. In contrast, lung and sarcoma cell lines were forced to undergo cell death upon p53 restoration when priming was increased by overexpression of the pro-apoptotic Bcl2 family members Bim or Bad. When transplanted subcutaneously, sarcoma cell lines expressing Bad were specifically sensitized to undergo cell death upon p53 restoration whereas cell lines expressing empty vector underwent cell cycle arrest. We are currently carrying out in vivo experiments with lymphoma cell lines and lung cell lines, as well as with autochthonous tumor models and human cell lines to further test our main hypothesis. These findings may offer key insights into the potential use of drugs that restore p53 function. Citation Format: Francisco J. Sánchez-Rivera, Jeremy Ryan, Yadira M. Soto-Feliciano, David M. Feldser, Michael T. Hemann, Anthony Letai, Tyler Jacks. The level of mitochondrial apoptotic priming determines cell fate upon p53 restoration. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2961. doi:10.1158/1538-7445.AM2014-2961