title: Proteomic analysis of INS-1 rat insulinoma cells: ER stress effects and the protective role of exenatide, a GLP-1 receptor agonist.
abstract: Beta cell death caused by endoplasmic reticulum (ER) stress is a key factor aggravating type 2 diabetes. Exenatide, a glucagon-like peptide (GLP)-1 receptor agonist, prevents beta cell death induced by thapsigargin, a selective inhibitor of ER calcium storage. Here, we report on our proteomic studies designed to elucidate the underlying mechanisms. We conducted comparative proteomic analyses of cellular protein profiles during thapsigargin-induced cell death in the absence and presence of exenatide in INS-1 rat insulinoma cells. Thapsigargin altered cellular proteins involved in metabolic processes and protein folding, whose alterations were variably modified by exenatide treatment. We categorized the proteins with thapsigargin initiated alterations into three groups: those whose alterations were 1) reversed by exenatide, 2) exaggerated by exenatide, and 3) unchanged by exenatide. The most significant effect of thapsigargin on INS-1 cells relevant to their apoptosis was the appearance of newly modified spots of heat shock proteins, thimet oligopeptidase and 14-3-3β, ε, and θ, and the prevention of their appearance by exenatide, suggesting that these proteins play major roles. We also found that various modifications in 14-3-3 isoforms, which precede their appearance and promote INS-1 cell death. This study provides insights into the mechanisms in ER stress-caused INS-1 cell death and its prevention by exenatide.
authors: Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea; Dong-A ST Research Institute, Yongin-si, Gyeonggi-do 446-905, Republic of Korea.
authors: Mi-Kyung
authors: MK
authors: Kim
authors: Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors: Jin-Hwan
authors: JH
authors: Cho
authors: Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors: Jae-Jin
authors: JJ
authors: Lee
authors: Dong-A ST Research Institute, Yongin-si, Gyeonggi-do 446-905, Republic of Korea.
authors: Moon-Ho
authors: MH
authors: Son
authors: Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors: Kong-Joo
authors: KJ
authors: Lee
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D000077270:Exenatide; D007340:Insulinoma / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D060066:Protein Interaction Maps; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D020543:Proteome; D040901:Proteomics; D051381:Rats; D019284:Thapsigargin / Q000494:pharmacology; D014688:Venoms / Q000494:pharmacology; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D048948:14-3-3 Proteins; D010455:Peptides; D020543:Proteome; D014688:Venoms; D019284:Thapsigargin; D000077270:Exenatide; D000097789:Glucagon-Like Peptide-1 Receptor Agonists