Abstract 5278: Superoxide mediated selective tyrosine nitration of protein phosphatase 2A-B56δ stabilizes Bcl-2 phosphorylation and its anti-apoptotic activity

Abstract

Abstract Our work over the years has provided strong evidence that an increase in intracellular superoxide anion provides cancer cells with a survival advantage and promotes tumor chemoresistance. The mechanisms underlying superoxide-mediated pro-survival signaling are poorly understood. Here we report that an increase in intracellular superoxide stabilizes the anti-apoptotic activity of Bcl-2 by mechanisms that involve sustained phosphorylation of Bcl-2 at serine 70. Of note, this effect on Bcl-2 S70 phosphorylation is a function of redox-dependent inactivation of Protein Phosphatase 2A (PP2A), which is targeted to Bcl-2 via its B56 subunit; superoxide induces the release of PP2A-AC catalytic core from Bcl-2-bound B56δ, resulting in sustained phosphorylation of Bcl-2 at S70. Dissociation of the PP2A heterotrimer results from the selective nitration (by peroxynitrite derived from the reaction of superoxide with NO) of a conserved tyrosine residue, which we identify as Y289 of B56δ (B56 δY289). Inhibition of B56δY289 nitration blocked the pro-survival effects of superoxide. Furthermore, we provide evidence for clinical relevance of these findings using primary tissue derived from human lymphoma biopsies. Taken together, these data provide evidence for a novel mechanism in which an increase in intracellular superoxide regulates PP2A function via specific B56 subunit tyrosine nitration, and that PP2A-B56 nitration may be a general mechanism for redox-regulated cellular signaling. Citation Format: Ivan C. C. Low, Thomas Loh, David Virshup, Shazib Pervaiz. Superoxide mediated selective tyrosine nitration of protein phosphatase 2A-B56δ stabilizes Bcl-2 phosphorylation and its anti-apoptotic activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5278. doi:10.1158/1538-7445.AM2014-5278