HSP90 acts as a senomorphic target in senescent retinal pigmental epithelial cells

• DOI: 10.18632/aging.203496
• Publication Date: 2021-09-08T18:59:31Z
• Authors: Dan-Dan Chen; Xuyan Peng; Yuxuan Wang; Mingjun Jiang; Mengjiao Xue; Guohui Shang; Xuhui Liu; Xiaolin Jia; Baixue Liu; Yingwei Lu; Hongmei Mu; Fengyan Zhang; Yanzhong Hu
• Keywords: 0303 health sciences; Cytokinins; Lactams, Macrocyclic; Epithelial Cells; Hydrogen Peroxide; Retinal Pigment Epithelium; Macaca mulatta; Retina; Cell Line; Macular Degeneration; 03 medical and health sciences; Senotherapeutics; Benzoquinones; Animals; Humans; HSP90 Heat-Shock Proteins; Cells, Cultured; Cellular Senescence; Research Paper

The senescence of retinal pigment epithelial (RPE) cells is associated with age-related macular degeneration (AMD), a leading cause of blindness in the world. HSP90 is a predominant chaperone that regulates cellular homeostasis under divergent physio-pathological conditions including senescence. However, the role of HSP90 in senescent RPE cells still remains unclear. Here, we reported that HSP90 acts as a senomorphic target of senescent RPE cells in vitro. Using H2O2-induced senescent ARPE-19 cells and replicative senescent primary RPE cells from rhesus monkey, we found that HSP90 upregulates the expression of IKKα, and HIF1α in senescent ARPE-19 cells and subsequently controls the induction of distinct senescence-associated inflammatory factors. Senescent ARPE-19 cells are more resistant to the cytotoxic HSP90 inhibitor IPI504 (IC50 = 36.78 μM) when compared to normal ARPE-19 cells (IC50 = 6.16 μM). Administration of IPI504 at 0.5-5 μM can significantly inhibit the induction of IL-1β, IL-6, IL-8, MCP-1 and VEGFA in senescent ARPE-19 and the senescence-mediated migration of retinal capillary endothelial cells in vitro. In addition, we found that inhibition of HSP90 by IPI504 reduces SA-β-Gal's protein expression and enzyme activity in a dose-dependent manner. HSP90 interacts with and regulates SA-β-Gal protein stabilization in senescent ARPE-19 cells. Taken together, these results suggest that HSP90 regulates the SASP and SA-β-Gal activity in senescent RPE cells through associating with distinctive mechanism including NF-κB, HIF1α and lysosomal SA-β-Gal. HSP90 inhibitors (e.g. IPI504) could be a promising senomorphic drug candidate for AMD intervention.