title: Molybdenum induces pancreatic β-cell dysfunction and apoptosis via interdependent of JNK and AMPK activation-regulated mitochondria-dependent and ER stress-triggered pathways.
abstract: Molybdenum (Mo), a well-known toxic environmental and industrial pollutant, causes adverse health effects and diseases in humans and has received attention as a potential risk factor for DM. However, the roles of Mo in the mechanisms of the toxicological effects in pancreatic β-cells are mostly unclear. In this study, the results revealed dysfunction of insulin secretion and apoptosis in the pancreatic β-cell-derived RIN-m5F cells and the isolated mouse islets in response to Mo. These effects were accompanied by a mitochondria-dependent apoptotic signals including a decreased in the MMP, an increase in cytochrome c release, and the activation of caspase cascades and PARP. In addition, ER stress was triggered as indicated by several key molecules of the UPR. Furthermore, exposure to Mo induced the activation of ERK1/2, JNK, AMPKα, and GSK3-α/β. Pretreatment with specific pharmacological inhibitors (in RIN-m5F cells and isolated mouse islets) of JNK (SP600125) and AMPK (Compound C) or transfection with si-RNAs (in RIN-m5F cells) specific to JNK and AMPKα effectively prevented the Mo-induced apoptosis and related signals, but inhibitors of ERK1/2 and GSK3-α/β (PD98059 and LiCl, respectively) did not reverse the Mo-induced effects. Additionally, both the inhibitors and specific si-RNAs could suppress the Mo-induced phosphorylation of JNK and AMPKα each other. Taken together, these results suggest that Mo exerts its cytotoxicity on pancreatic β-cells by inducing dysfunction and apoptosis via interdependent JNK and AMPK activation downstream-regulated mitochondrial-dependent and ER stress-triggered apoptosis pathways.
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan.
authors.forename: Tsung-Yuan
authors.initials: TY
authors.lastname: Yang
authors.affiliation: Department of Occupational Safety and Health, College of Health Care and Management, Chung Shan Medical University, Taichung 402, Taiwan; Department of Occupational Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan.
authors.forename: Cheng-Chieh
authors.initials: CC
authors.lastname: Yen
authors.affiliation: Department of Emergency, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, Taiwan.
authors.forename: Kuan-I
authors.initials: KI
authors.lastname: Lee
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua County 500, Taiwan; Graduate Institute of Basic Medical Science, School of Medicine, College of Medicine, China Medical University, Taichung 404, Taiwan.
authors.forename: Chin-Chuan
authors.initials: CC
authors.lastname: Su
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan; Department of Surgery, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Ching-Yao
authors.initials: CY
authors.lastname: Yang
authors.affiliation: Department of Public Health, China Medical University, Taichung 404, Taiwan.
authors.forename: Chin-Ching
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Department of Emergency, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, Taiwan. Electronic address: gile1123@yahoo.com.tw.
authors.forename: Shang-Shu
authors.initials: SS
authors.lastname: Hsieh
authors.affiliation: Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan; School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan. Electronic address: kcueng@gmail.com.
authors.forename: Kwo-Chang
authors.initials: KC
authors.lastname: Ueng
authors.affiliation: School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan. Electronic address: cfhuang@mail.cmu.edu.tw.
authors.forename: Chun-Fa
authors.initials: CF
authors.lastname: Huang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects*; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D053612:Janus Kinases / Q000187:drug effects*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology*; D008982:Molybdenum / Q000494:pharmacology*; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D034741:RNA, Small Interfering; D008982:Molybdenum; D053612:Janus Kinases; D055372:AMP-Activated Protein Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: AMPK; Apoptosis; ER stress; JNK; Molybdenum; Pancreatic β-cells