Squamosamide Derivative FLZ Protects Retinal Pigment Epithelium Cells from Oxidative Stress through Activation of Epidermal Growth Factor Receptor (EGFR)-AKT Signaling

International Journal of Molecular Sciences

Li-Bo Cheng¹  Chun-Ming Chen¹  Hong Zhong²  Li-Juan Zhu¹ 

[1] Eye Department, Li-yang City Hospital of Traditional Chinese Medicine, Li-Yang City 213300, China;

关键词: age-related macular degeneration (AMD);    retinal pigment epithelium (RPE);    squamosamide derivative FLZ;    apoptosis;    AKT signaling and EGFR (epidermal growth factor receptor) trans-activation;   

DOI  :  10.3390/ijms151018762

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.