THE EFFECT OF REDOX-INACTIVATION OF PP2A ON BCL-2 AND P53

Abstract

The cellular redox environment is regulated by the antioxidant defence system under homeostatic growth. The disruption, particularly inhibition, of this system may result to a range of moderate to highly elevated intracellular ROS milieus. Importantly, the increase in ROS levels have been implicated in a multitude of cellular events ranging from cell survival to oxidative stress and apoptosis. To these ends, we have unravelled two distinct oncogenic mechanisms that allow cancer cells to adapt to such biphasic ROS characteristics. In chapter 1, we demonstrated that the accumulation of Bcl-2 phosphorylation, induced by ROS-dependent inactivation of PP2A, results to a protective feedback against drug-induced oxidative stress. In chapter 2, we demonstrated that a mild increase in intracellular ROS level is capable of desensitizing cancer cells towards chemotherapeutic-induced cell death. This was again a function of ROS-dependent inactivation of PP2A, leading to the accumulated p53 phosphorylation and its subsequent inactivation. In all, our work demonstrates two novel yet distinct mechanisms, which provide advantages for cancer cells to adapt to various intracellular ROS milieus.