Abstract 3811: Arsenic trioxide induces cell cycle arrest, apoptosis through interaction of DAXX and degradation of MDM2 in acute leukemia cells

Abstract

Abstract Arsenic trioxide (ATO) alone or combination with all trans retinoic acid (ATRA) has been successfully used in the treatment of all age group of acute promyelocytic leukemia (APL) patients. Recent human clinical trails result of ATO and their combination with ATRA shown complete remission in both de novo and relapsed APL patients. However, the detailed molecular mechanisms of its anti-leukemic action through cell cycle arrest and apoptosis are poorly known. We have used APL cell line and transgenic mice model to elucidate the anti-cancer properties of arsenic trioxide. We hypothesized that ATO arrests cell cycle and apoptosis through activation of p53 and interaction of death domain-associated protein (DAXX), which disrupted the MDM2-DAXX-HAUSP interactions. It also promoted MDM2 self-ubiquitination and degradation. To test the hypothesis, we used western blotting, confocal imaging and other molecular techniques to identify detailed cellular and molecular mechanisms of ATO action in APL cells and transgenic mice hepatocytes as well as bone marrow cells. We found that the expression levels of p53 and p21 increased significantly, whereas MDM2, DAXX and HAUSP decreased dose dependent manner. Our immunoprecipitation (IP) studies shown that they are well associated each other in cells and ATO disrupts associations. After 21 days treatment of ATO different doses (1.25, 2.5, 5.0 and 7.5 mg/kg body wt) in transgenic mice, we have collected liver tissue and isolated hepatocytes and bone marrow. In liver tissue, we found p53 nicely activated dose dependent ATO treated mice. On the basis of these findings, we conclude that ATO induces cell cycle arrest and apoptosis in APL cell line as well as mice hepatocytes through p53 activation, MDM2 self-ubiquitination and disruption of MDM2-DAXX-HAUSP interaction. It is novel target for treatment of APL patients through designing of new anti-leukemic drugs. Keywords: Arsenic trioxide, HL-60 cells, cell cycle arrest, apoptosis, mitochondrial pathway, Mice hepatocytes and bone marrow. Acknowledgements: This research was financially supported by National Institutes of Health NCRR Grant No. 5G12RR013459 and MIMHD Grant No. 8G12MD007581, through the RCMI-Center for Environmental Health at Jackson State University. Citation Format: Sanjay Kumar, Paul B. Tchounwou. Arsenic trioxide induces cell cycle arrest, apoptosis through interaction of DAXX and degradation of MDM2 in acute leukemia cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3811. doi:10.1158/1538-7445.AM2015-3811