title: Squamosamide derivative FLZ protects retinal pigment epithelium cells from oxidative stress through activation of epidermal growth factor receptor (EGFR)-AKT signaling.
abstract: Reactive oxygen species (ROS)-mediated retinal pigment epithelium (RPE) cell apoptosis is attributed to age-related macular degeneration (AMD) pathogenesis. FLZ, a novel synthetic squamosamide derivative from a Chinese herb, Annona glabra, has displayed significant cyto-protective activity. In the current study, we explored the pro-survival effect of FLZ in oxidative stressed-RPE cells and studied the underlying signaling mechanisms. Our results showed that FLZ attenuated hydrogen peroxide (H2O2)-induced viability decrease and apoptosis in the RPE cell line (ARPE-19 cells) and in primary mouse RPE cells. Western blotting results showed that FLZ activated AKT signaling in RPE cells. The AKT-specific inhibitor, MK-2206, the phosphoinositide 3-kinase (PI3K)/AKT pan inhibitor, wortmannin, and AKT1-shRNA (short hairpin RNA) depletion almost abolished FLZ-mediated pro-survival/anti-apoptosis activity. We discovered that epidermal growth factor receptor (EGFR) trans-activation mediated FLZ-induced AKT activation and the pro-survival effect in RPE cells, and the anti-apoptosis effect of FLZ against H2O2 was inhibited by the EGFR inhibitor, PD153035, or by EGFR shRNA-knockdown. In conclusion, FLZ protects RPE cells from oxidative stress through activation of EGFR-AKT signaling, and our results suggest that FLZ might have therapeutic values for AMD.
authors.affiliation: Eye Department, Li-yang City Hospital of Traditional Chinese Medicine, Li-Yang City 213300, China. dryaojin@yahoo.com.
authors.forename: Li-Bo
authors.initials: LB
authors.lastname: Cheng
authors.affiliation: Eye Department, Li-yang City Hospital of Traditional Chinese Medicine, Li-Yang City 213300, China. chunmingchenapp@163.com.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Chen
authors.affiliation: Eye Department, Li-yang City Hospital of Traditional Chinese Medicine, Li-Yang City 213300, China. hongapple126@126.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Eye Department, Li-yang City Hospital of Traditional Chinese Medicine, Li-Yang City 213300, China. caocong1111@hotmail.com.
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Zhu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D044482:Benzeneacetamides / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects*; D010636:Phenols / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D044482:Benzeneacetamides; D010636:Phenols; D017382:Reactive Oxygen Species; C084439:squamosamide; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt