Abstract 5239: Cisplatin disrupts MDM2-DAXX-HAUSP complex, p53 accumulation, cell cycle regulation, and apoptosis in acute leukemia cells

Abstract

Cisplatin (CDDP) is an antitumor drug successfully used in the treatment of various types of human malignancies. It enhances toxicity of arsenic trioxide (ATO) in head and neck squamous cell carcinoma cell, small cell lung cancer, ovarian cancer cells, and oral squamous cell carcinoma cells (, and chronic myelogenous leukemia cells. CDDP induces cytotoxicity, DNA damage, oxidative stress, and apoptosis in acute promyelocytes leukemia (APL) cells. However, the molecular mechanisms of CDDP-induced P53 activation, cell cycle arrest, and apoptosis in APL cells remain poorly understood. We hypothesized that CDDP inhibits proliferation of APL cells through MDM2-DAXX-HAUSP complex disruption, p53 activation leading to cell cycle arrest and apoptosis. To test hypothesis, we used three APL cell lines and mice model of APL and investigated CDDP effects on cells growth, complex disruption, cell cycle progression, and apoptosis by applying western blotting, IP, gene knockdown techniques, immune/histochemistry, and confocal imaging. We found that CDDP - induced stress signal transmitted by protein kinase (ATM, ATR) and its downstream targets (CHK1 & CHK2) phosphorylation leading to down-regulation of complex molecules expression and accumulation of p53. CDDP-induced p53 expression modulated cell cycle progression and apoptosis in APL cells, and stimulated the formation of more promyelocytes with dense granules through reduction of MDM2 expression in bone marrow cells. CDDP also activated p53 in APL mice liver tissues. This novel mechanism of action of CDDP in APL cells may help in the design of new anti-leukemic drugs for treatment of APL patients. Acknowledgements: This research was supported by National Institutes of Health NIMHD [grant # G12MD007581], through the RCMI-Center for Environmental Health at Jackson State University. Citation Format: Sanjay Kumar, Paul Tchounwou. Cisplatin disrupts MDM2-DAXX-HAUSP complex, p53 accumulation, cell cycle regulation, and apoptosis in acute leukemia cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5239.