title: Gossypol Acetic Acid Prevents Oxidative Stress-Induced Retinal Pigment Epithelial Necrosis by Regulating the FoxO3/Sestrin2 Pathway.
abstract: 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 a 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 U.S. Food and Drug Administration-approved natural compounds and identified gossypol acetic acid (GAA) as a potent inhibitor of oxidative stress-induced RPE cell death. GAA induces antioxidative response and inhibits accumulation of excessive reactive oxygen species in cells, through which it prevents the activation of intrinsic necrotic pathway in response to oxidative stress. Sestrin2 (SESN2) is found to mediate GAA function in antioxidative response and RPE survival upon oxidative stress. Moreover, Forkhead box O3 transcription factor (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. Taken together, we have identified GAA as a potent inhibitor of oxidative stress-induced RPE necrosis by regulating the FoxO3/SESN2 pathway. This study may have significant implications in the therapeutics of age-related diseases, especially GA.
authors: Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA.
authors: Jakub
authors: J
authors: Hanus
authors: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Hongmei
authors: H
authors: Zhang
authors: Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA.
authors: David H
authors: DH
authors: Chen
authors: Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA.
authors: Qinbo
authors: Q
authors: Zhou
authors: Department of Human Genetics, School of Medicine, Emory University, Atlanta, Georgia, USA.
authors: Peng
authors: P
authors: Jin
authors: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Qinghua
authors: Q
authors: Liu
authors: Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA Department of Ophthalmology, Tulane University, New Orleans, Louisiana, USA swang1@tulane.edu.
authors: Shusheng
authors: S
authors: Wang
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics*; D006072:Gossypol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008268:Macular Degeneration / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009336:Necrosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism; D012168:Retinal Pigments / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014481:United States; D014486:United States Food and Drug Administration; D000084622:Sestrins
chemical_list: D000975:Antioxidants; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D006072:Gossypol; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D012168:Retinal Pigments; C499517:FOXO3 protein, human; C465398:SESN2 protein, human; D000084622:Sestrins; C028178:gossypol acetic acid