Squamosamide derivative FLZ protects retinal pigment epithelium cells from oxidative stress through activation of epidermal growth factor receptor (EGFR)-AKT signaling

• Published in: International journal of molecular sciences 2014-10, Vol.15 (10), p.18762-18775
• Main Authors: Cheng, Li-Bo, Chen, Chun-Ming, Zhong, Hong, Zhu, Li-Juan
• Format: Article
• Language: English
• Subjects: age-related macular degeneration (AMD); AKT signaling and EGFR (epidermal growth factor receptor) trans-activation; Animals; Annona glabra; apoptosis; Apoptosis - drug effects; Benzeneacetamides - pharmacology; Cell Line; Cell Survival - drug effects; Cells, Cultured; Epidermal growth factor; Humans; Hydrogen Peroxide - metabolism; Macular degeneration; Mice; Mice, Inbred C57BL; Oxidative stress; Oxidative Stress - drug effects; Phenols - pharmacology; Phosphatidylinositol 3-Kinases - metabolism; Phytochemicals; Pigments; Proto-Oncogene Proteins c-akt - metabolism; Reactive Oxygen Species - metabolism; Receptor, Epidermal Growth Factor - metabolism; Retina; retinal pigment epithelium (RPE); Retinal Pigment Epithelium - cytology; Retinal Pigment Epithelium - drug effects; Retinal Pigment Epithelium - metabolism; Signal Transduction - drug effects; squamosamide derivative FLZ
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms151018762

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.