title: Activation of eIF2α signaling cascade is associated with testosterone-induced cell apoptosis in INS-1 cells.
abstract: 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 β-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 β-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 (eIF2α) 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 eIF2α/CHOP cascades.
authors.affiliation: Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory for Assisted -Reproduction and Reproductive Genetics, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.affiliation: Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Qilu Hospital of Shandong University, Jinan, China.
authors.forename: H
authors.initials: H
authors.lastname: Guo
authors.affiliation: Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory for Assisted -Reproduction and Reproductive Genetics, Shanghai, China.
authors.forename: Z-J
authors.initials: ZJ
authors.lastname: Chen
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005485:Flutamide / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000378:metabolism; D008297:Male; D010654:Phenylbutyrates / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013739:Testosterone / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D010654:Phenylbutyrates; D051028:bcl-2-Associated X Protein; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D013739:Testosterone; D005485:Flutamide; C075773:4-phenylbutyric acid