Shusheng Wang
Tulane University, USA
Posters-Accepted Abstracts: Nat Prod Chem Res
The late stage of dry Age-Related Macular Degeneration (AMD) or Geographic Atrophy (GA) is characterized by extensive Retinal Pigment Epithelial (RPE) cell death and the cure is not available currently. We have recently demonstrated that RPE cells die from necrosis in response to oxidative stress, providing a potential novel mechanism for RPE death in AMD. In this study, we screened FDA-approved natural compounds for their ability to prevent oxidative stress-induced RPE death. We identified Gossypol Acetic Acid (GAA) as a potent inhibitor of oxidative stress-induced RPE cell death. GAA induces anti-oxidative response and inhibits accumulation of excessive Reactive Oxygen Species (ROS) in cells, through which it prevents the activation of intrinsic necrotic pathway in response to oxidative stress. Sestrin2 (SESN2) gene is found to be sufficient and necessary for mediating GAA function in anti-oxidative response and RPE survival upon oxidative stress. Moreover, FoxO3 is further found to be required for GAA mediated SESN2 expression and RPE survival. Mechanistically, GAA promotes FoxO3 nuclear translocation and binding to the SESN2 enhancer, which in turn increases its transcriptional activity. This establishes a critical role for FoxO3/SESN2 axis in regulating RPE survival in response to oxidative stress. Taken together, we have identified GAA as a potent inhibitor of oxidative stress-induced RPE necrosis by regulating FoxO3/SESN2 pathway. This study may have significant implication in the therapeutics of age-related diseases, especially GA.
Email: swang1@tulane.edu
