P-9 - Bcl-2 phosphorylation at serine-70 protects cancer cells from ROS-induced DNA damage and cell death by engaging the mitochondrial respiratory system

Abstract

Chemotherapeutics target cancer cells by inducing DNA damage. The mechanism of these drugs in damaging DNA relies partly in the elevation of ROS, which in turn causes DNA oxidation, strand breaks and cell death. Although cancer cells are capable of resisting drug-induced cell death by various protective means, the mechanism that specifically rely on modulating the redox milieu, in favor of survival, is not fully elucidated. We now show that phosphorylation of the anti-apoptotic Bcl2 at Serine70 (S70pBcl2), could alleviate drug-induced DNA damage to prevent cancer cell death. This is due to its ability in preventing drug-induced intracellular ROS production. Mechanistically, S70pBcl2 resulted in a diminished interaction between Bcl2 and cytochrome c oxidase subunit Vα (COX5α), a mitochondrial complex VI subunit, as well as Bcl2-dependent shuttling of COX5α to the mitochondria. This in turn reduces complex IV activity, mitochondrial oxygen consumption and ultimately mitochondrial O2- production. Importantly, the inverse correlation between S70pBcl2 and Bcl2/COX5α interaction as well as DNA damage were recapitulated in clinical lymphomas. These data underscore the oncogenic and antioxidant roles of Bcl2 phosphorylation in protecting cancer cells from DNA damage-induced cell death.