Superoxide anion is Implicated in the Regulation of PP2A-B56?-mediated Dephosphorylation of Bcl-2

Abstract

A high intracellular O2-:H2O2 ratio has been shown to favor survival signaling in tumour cells. However, exactly how O2- signals for cell survival is still unknown. Here, we demonstrate, both in vivo and in vitro, that an elevated intracellular O2- level induced by either DDC-mediated inhibition of SOD1 or SiRNA-mediated downregulation of SOD1 resulted in the increased phosphorylation of Bcl-2 specifically at Ser70, which in turn enhanced the antiapoptotic activity of Bcl-2. O2- induced Ser70 Bcl-2 phosphorylation was further shown to be due to a disruption in B56d-containing PP2A holoenzyme assembly, which in turn, was shown to be due to a selective nitration of B56d at Tyr289 (by peroxynitrite derived from the reaction of O2- with NO) that inhibited B56d-mediated recruitment of the PP2A AC-catalytic core to Bcl-2. Taken together, our data demonstrate a novel mechanism in which an elevated O2-:H2O2 ratio could augment chemoresistance of cancer cells.