Abstract A52: Paracrine apoptotic effect of the tumor suppressor p53 is mediated by secreted Par-4

Abstract

Abstract The guardian of the genome, p53, is mutated or functionally inactivated in a majority of human cancers. However, p53 in normal cells is intact and functional. In the present study, we tested the potential of wild-type p53 in normal tissues to inhibit the growth of p53-deficient cancer cells. Co-culture experiments of normal fibroblasts with cancer cells revealed that specific activation of p53 in normal fibroblasts selectively induced apoptosis in p53-deficient cancer cells. Moreover, this paracrine apoptotic effect of p53 was attributed to an enhanced secretion of the tumor suppressor Par-4 in response to p53 activation. Mechanistically, p53 represses the expression of UACA, a binding partner of Par-4, by directly binding to its signature motif in the UACA gene. Down-regulation of UACA expression liberates Par-4 from sequestration, and thus induces its secretion. Consistent with our cell culture studies, animal experiments also show that activation of p53 results in an elevation of systemic Par-4 levels in p53+/+ mice, which can induce apoptosis in p53-deficient cancer cells in ex vivo experiments. By contrast, p53 activators failed to induce this paracrine effect in p53-/- or Par-4-/- mice. Thus, by activating wild-type p53, normal cells can be empowered to inhibit tumor growth, progression, and metastasis. Citation Format: Tripti Shrestha-Bhattarai, Ravshan Burikhanov, Nikhil Hebbar, Shirley Qiu, Yanming Zhao, Gerard P. Zambetti, Vivek M. Rangnekar. Paracrine apoptotic effect of the tumor suppressor p53 is mediated by secreted Par-4. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A52. doi:10.1158/1538-7445.CHTME14-A52