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Int. J. Mol. Sci. 2014, 15(10), 18762-18775; doi:10.3390/ijms151018762

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

Eye Department, Li-yang City Hospital of Traditional Chinese Medicine, Li-Yang City 213300, China
These authors contributed equally to this work.
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Received: 3 June 2014 / Revised: 2 September 2014 / Accepted: 11 September 2014 / Published: 17 October 2014
(This article belongs to the Collection Programmed Cell Death and Apoptosis)
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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. View Full-Text
Keywords: age-related macular degeneration (AMD); retinal pigment epithelium (RPE); squamosamide derivative FLZ; apoptosis; AKT signaling and EGFR (epidermal growth factor receptor) trans-activation age-related macular degeneration (AMD); retinal pigment epithelium (RPE); squamosamide derivative FLZ; apoptosis; AKT signaling and EGFR (epidermal growth factor receptor) trans-activation
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Cheng, L.-B.; Chen, C.-M.; Zhong, H.; Zhu, L.-J. Squamosamide Derivative FLZ Protects Retinal Pigment Epithelium Cells from Oxidative Stress through Activation of Epidermal Growth Factor Receptor (EGFR)-AKT Signaling. Int. J. Mol. Sci. 2014, 15, 18762-18775.

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