title: Nickel(II) induced JNK activation-regulated mitochondria-dependent apoptotic pathway leading to cultured rat pancreatic β-cell death.
abstract: Nickel (Ni), a well-known toxic metal, is widely used in electroplating and alloy production. It is also significantly implicated in industrial and environmental pollution caused by uncontrolled industrial and municipal discharges. In this study, we characterized and investigated the cytotoxic effects of Ni exposure and their probable toxicological mechanisms in the pancreatic β-cells. The results showed that it was significantly decreased cell viability after exposing pancreatic β-cell-derived RIN-m5F cells to NiCl(2) for 24h in a dose-dependent manner. NiCl(2) also increased sub-G1 hypodiploid cells and Annexin V-Cy3 binding population in RIN-m5F cells, indicating that it has apoptosis-inducing ability. Moreover, the exposure of RIN-m5F cells to NiCl(2) induced distinct signals of mitochondria-dependent apoptosis, including mitochondrial dysfunction (the disruption of mitochondrial membrane potential (MMP) and increase in mitochondrial cytochrome c release into the cytosol), Bak and Bid mRNA up-regulation, and activation of caspase-3, caspase-7, and caspase-9, and poly(ADP-ribose) polymerase (PARP) degradation. In addition, NiCl(2) also markedly induced the activation of c-Jun N-terminal kinases (JNK), but not of extracellular signal-regulated kinase (ERK)1/2 and p38. These NiCl(2)-induced apoptosis-related signaling responses could be effectively reversed by specific JNK inhibitor SP600125. To the best of our knowledge, this study is the first to show that Ni causes pancreatic β-cell death through a JNK activation-regulated mitochondria-dependent apoptosis-signaling pathway.
authors.affiliation: Department of Urology, China Medical University Hospital, No. 2, Yuh-Der Rd., Taichung 404, Taiwan.
authors.forename: Hsi-Chin
authors.initials: HC
authors.lastname: Wu
authors.forename: Ching-Yao
authors.initials: CY
authors.lastname: Yang
authors.forename: Dong-Zong
authors.initials: DZ
authors.lastname: Hung
authors.forename: Chin-Chuan
authors.initials: CC
authors.lastname: Su
authors.forename: Kuo-Liang
authors.initials: KL
authors.lastname: Chen
authors.forename: Cheng-Chieh
authors.initials: CC
authors.lastname: Yen
authors.forename: Tsung-Jung
authors.initials: TJ
authors.lastname: Ho
authors.forename: Yi-Chang
authors.initials: YC
authors.lastname: Su
authors.forename: Chun-Fa
authors.initials: CF
authors.lastname: Huang
authors.forename: Chun-Hung
authors.initials: CH
authors.lastname: Chen
authors.forename: Ling-Mei
authors.initials: LM
authors.lastname: Tsai
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000201:enzymology; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009532:Nickel / Q000633:toxicity*; D051381:Rats
chemical_list: D009532:Nickel; D048031:JNK Mitogen-Activated Protein Kinases