MHY1485 ameliorates UV-induced skin cell damages via activating mTOR-Nrf2 signaling.

Bo Yang,Ying Tu,Zhi-Gang Bi,Qiu-Yun Xu,Li He,Shu-Mei Wang,Bo Cheng,Chun-Yan Guo,Jin-Wen Huang,Yong-Mei Li,Chao Ji

doi:10.18632/oncotarget.14299

Abstract

Ultra Violet (UV)-caused skin cell damage is a main cause of skin cancer. Here, we studied the activity of MHY1485, a mTOR activator, in UV-treated skin cells. In primary human skin keratinocytes, HaCaT keratinocytes and human skin fibroblasts, MHY1485 ameliorated UV-induced cell death and apoptosis. mTOR activation is required for MHY1485-induced above cytoprotective actions. mTOR kinase inhibitors (OSI-027, AZD-8055 and AZD-2014) or mTOR shRNA knockdown almost abolished MHY1485-induced cytoprotection. Further, MHY1485 treatment in skin cells activated mTOR downstream NF-E2-related factor 2 (Nrf2) signaling, causing Nrf2 Ser-40 phosphorylation, stabilization/upregulation and nuclear translocation, as well as mRNA expression of Nrf2-dictated genes. Contrarily, Nrf2 knockdown or S40T mutation almost nullified MHY1485-induced cytoprotection. MHY1485 suppressed UV-induced reactive oxygen species production and DNA single strand breaks in skin keratinocytes and fibroblasts. Together, we conclude that MHY1485 inhibits UV-induced skin cell damages via activating mTOR-Nrf2 signaling.

Highlights

Ultra Violet (UV) radiation in skin keratinocytes and fibroblasts would lead to oxidative stress and DNA damages, along with activation of several signal transduction pathways that are important for cancer initiation and progression [1,2,3]
Primary cultured human skin keratinocytes [7] were irradiated with UV (20 mJ/cm2), MTT assay results in Figure 1A showed that cell survival (MTT optic density (OD)) was decreased sharply following UV radiation
We found that MHY1485 activated mammalian target of rapamycin (mTOR) and significantly attenuated UV-induced death and apoptosis of skin keratinocytes, HaCaT keratinocytes and skin fibroblasts

Summary

Introduction

Ultra Violet (UV) radiation in skin keratinocytes and fibroblasts would lead to oxidative stress and DNA damages, along with activation of several signal transduction pathways that are important for cancer initiation and progression [1,2,3]. Mammalian target of rapamycin (mTOR) is a vital pro-survival signaling [10]. MTORC1 shall be inhibited by rapamycin or its analogs, and is formed with mTOR, Raptor, mLST8 and several others [10,11,12]. MTORC1 phosphorylates p70S6K1 (S6K1) and eukaryotictranslation initiation factor 4E-binding protein 1 (4E-BP1) to promote protein translation, energy metabolism and cell survival [11, 13]. The complex serves as the upstream kinase of Akt (Ser-473), a major pro-survival signaling [11, 13]. It has been increasingly clear that both complexes are important for cell survival [10, 12]

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