133 - Tumor Pro-oxidant Enviroment Stabilizes Onco-protein c-Myc via Sustained Phosphorylation at Serine 62 that Promotes its Oncogenic Activity

Abstract

c-Myc is arguably one of the most notorious oncoproteins known. c-Myc activity and oncogenic potential, are in turn, intricately regulated by its stabilizing phosphorylation at the Serine 62 (S62) residue. Phosphorylation at the S62 site is mediated by RAS activated RAF/MEK/ERK signaling cascade, while its dephosphorylation is under the governance of the protein phosphatase 2A (PP2A). Our recent work highlighted the critical involvement of cellular redox status, in particular superoxide anion, in inhibiting PP2A-mediated dephosphorylation of Bcl-2 at serine 70, thus stabilizing its anti-apoptotic activity1. Here we report that the stabilization and activity of the onco-protein c-myc is significantly amplified by the 'pro-oxidant' tumor microenvironment, which profoundly impacted PP2A phosphatase activity via nitrative inhibition of the B56α regulatory subunit. The B56α regulatory arm is responsible for delivering PP2A substrate phosphoprotein-c-Myc to the catalytic C subunit within the AC core dimer. Tyrosine nitration of the B56α isoform renders it incapable of binding the core dimer causing c-Myc to remain hyperphosphorylated at the serine 62 site. Sustained serine 62 phosphorylated c-Myc inhibits its ubiquitination and degradation by the 26S proteasome. Hitherto driven c-Myc stability is further complemented with a moderate increase in its activity and gain of chemoresistance in osteosarcoma cells. This paradigm shift in our understanding of c-Myc stability as a function of tumor redox microenvironment could give us valuable cues in providing a pathway for therapeutic intervention targeting post-translational regulation of c-Myc in human cancer.