Activation of eIF2α Signaling Cascade is Associated with Testosterone-Induced Cell Apoptosis in INS-1 Cells

Hyperandrogenemia is associated with insulin resistance and type 2 diabetes in women with polycystic ovary syndrome raising the possibility that androgen receptor signaling pathway plays an important role in the development and progression of beta-cell dysfunction. Testosterone is the major circulating androgen in women. In this study, we investigated the effect of testosterone on INS-1 cells to find whether excess androgen could produce endoplasmic reticulum (ER) stress thereby contributing to beta-cell dysfunction. The role of testosterone in INS-1 cell apoptosis was detected by flow cytometry and electron microscopy. Expression of BIP, ATF4, and CHOP were assessed by RT-PCR and Western blot. Testosterone/AR could not only initiate cell apoptosis but also induce the activation of eukaryotic initiation factor 2 alpha (eIF2 alpha) cascades in INS-1 cells. Treatment of ER stress inhibitor or flutamide (AR inhibitor) could inhibit testosterone-induced cell apoptosis and CHOP expression. These results suggest that testosterone/AR pathway caused INS-1 cell apoptosis was at least in part through eIF2a/CHOP cascades. Supporting Information for this article is available online at http://www.thieme-connect.de/ejournals/toc/hmr