Abstract 1580: Differential induction of reactive oxygen species by histone deacetylase inhibitors for mediating selective apoptosis of oncogenic H-Ras-expressing cells

Abstract

Abstract This study is to understand the mechanisms involved in the reactive oxygen species (ROS)-mediated pro-apoptotic ability of H-Ras to enhance apoptosis induced by histone deacetylase inhibitors (HDACIs). Oncogenic induction of the ras genes is widely involved in human cancers. Expression of oncogenic H-Ras increases susceptibility of human and mouse cells to HDACIs, such as FK228 and trichostatin A, for inducing caspase activation and selective apoptosis. To understand the mechanisms for HDACI-induced differential activation of caspases and apoptosis in oncogenic H-Ras-expressing cells, we investigated the role and regulation of ROS in HDACI-induced cell death. We detected that expression of oncogenic H-Ras resulted in potentiating intracellular ROS machinery, increasing the susceptibility to HDACIs for enhancing the production of ROS, and depleting glutathione, leading to differential activation of caspases and cell death. Furthering our understanding of how oncogenic H-Ras augmented the generation of ROS, we detected that expression of oncogenic H-Ras was able to increase the level of Nox1, a homologue of the catalytic subunit of the superoxide-generating NADPH oxidase. Suppression of Nox1 by the specific inhibitor diphenylene iodonium or specific siRNAs significantly reduced ROS production induced by oncogenic H-Ras and HDACIs as well as HDACI-induced cell death of oncogenic H-Ras-expressing cells. Our results led us to a suggestion that increased ROS played a contributing role in the proapoptotic ability of oncogenic H-Ras to enhance HDACI-induced activation of caspases for inducing selective apoptosis in a dose-dependent manner; Nox1 played an important role in the ability of oncogenic H-Ras to potentiate ROS-producing machinery for enhancing cell susceptibility to HDACIs and, in turn, increasing ROS contents leading to caspase activation and selective apoptosis. Differential increases of intracellular ROS by oncogenic H-Ras to potentiate cell death should be seriously considered as a potential target in developing therapeutic strategies to control oncogenic H-Ras-involved human cancers by HDACIs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1580.