Abstract 1681: Synergistic induction of Mek1/2 and Nox-1 by histone deacetylase inhibitors leads to differential induction of reactive oxygen species for mediating selective apoptosis of oncogenic H-Ras-expressing cells

Abstract

Abstract The goal of this study was to investigate roles of the ERK pathway and Nox-1 in the pro-apoptotic ability of oncogenic H-Ras to enhance histone deacetylase inhibitor (HDACI)-induced cell death. Oncogenic induction of the ras genes is widely involved in human cancers. Our previous studies revealed that expression of oncogenic H-Ras increases susceptibility of human and mouse cells to HDACIs, such as FK228 and trichostatin A, for inducing selective apoptosis. In this study, we used the mouse embryo fibroblast 10T1/2-TR-H-ras cell system, in which ectopic expression of oncogenic H-Ras(V12) is controlled by addition of tetracycline into cultures, and paired oncogenic H-Ras-expressing and parental human epithelial cells. We pursued the roles of Mek1/2 activation, Nox-1 elevation, and reactive oxygen species (ROS) production in FK228-induced selective cell death of oncogenic H-Ras-expressing cells versus counterpart cells. We verified that Nox-1 elevation and ROS played essential roles in oncogenic H-Ras-induced cell proliferation and morphological transformation. We also detected that FK228 treatment and expression of oncogenic H-Ras synergistically induced Mek1/2 activation, leading to differentially elevated Nox-1 and ROS and contributing to induction of selective apoptosis of oncogenic H-Ras-expressing cells versus counterpart cells. FK228 treatment also resulted in mitochondrial ROS production, and mitochondrial ROS contributed to Mek1/2 activation, bypassing Raf, to induce Erk1/2 activation for elevating Nox-1 and ROS, leading to apoptosis. Accordingly, Mek1/2 and Nox-1 played important pro-apoptotic roles in ROS-mediated cell death. Thus, Mek1/2 and Nox-1 should be considered as potential targets in designing therapeutic protocols using FK228 in ROS-mediated cell killing to treat cancer cells acquiring Ras activation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1681. doi:10.1158/1538-7445.AM2011-1681