Abstract 1323: A p53-dependent switch between cytoprotective and nonprotective autophagy influences tumor cell sensitivity to cisplatin

Abstract

Abstract Autophagy is a multi-step, homeostatic process through which cells turnover dysfunctional organelles and proteins. Previous work in our laboratory has identified multiple functional roles of autophagy, specifically cytoprotective, cytotoxic, cytostatic and nonprotective, when subjected to radiation and chemotherapy. Furthermore, we have reported on the existence of an autophagic switch between one functional form (generally cytoprotective) to the other forms. To further explore the autophagic switch, we utilized p53 wild type (p53 +/+) and p53 null (p53 -/-) H460 non-small cell lung cancer (NSCLC) cell lines exposed to cisplatin. The extent of autophagy was similar in both cell lines, but the rate and extent of apoptosis was higher in the p53 +/+ cells, which showed greater cisplatin sensitivity. Pharmacological (chloroquine, 3-Methyladenine) and genetic (ATG5 silencing) inhibition of autophagy failed to sensitize the p53 +/+ H460 cells to cisplatin, suggesting that autophagy has a nonprotective role. In contrast, autophagy inhibition (CQ, 3-MA, or shATG5) increased sensitivity to cisplatin in the p53 -/- H460 cells, indicative of a cytoprotective function of autophagy. These studies support the premise that cytoprotective autophagy may confer resistance to cisplatin. Moreover, we confirm the pivotal role of p53 in determining the function of autophagy induced by cisplatin. Finally, we provide an additional example of a switch between the nonprotective and protective forms of autophagy in p53 wild type and p53 null H460 non-small cell lung cancer (NSCLC) cells, respectively. Citation Format: Jingwen Xu, Tareq Saleh, Nipa Patel, Yingliang Wu, Santiago Lima, David Gewirtz. A p53-dependent switch between cytoprotective and nonprotective autophagy influences tumor cell sensitivity to cisplatin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1323.