title: Etoposide induces pancreatic β-cells cytotoxicity via the JNK/ERK/GSK-3 signaling-mediated mitochondria-dependent apoptosis pathway.
abstract: Etoposide is widely used in the treatment of the different types of tumors such as pancreatic cancer. However, etoposide also causes several unwanted side-effects in normal viable cells, including pancreatic β-cells, which are vulnerable to chemical-induced injuries, and the molecular mechanisms underlying etoposide-induced apoptosis are still unclear. Here, the results showed that in RIN-m5F cells (a β-cell-derived cell line), the number of viable cells was significantly decreased after 24h of etoposide treatment and underwent mitochondria-dependent apoptotic signals accompanied by mitochondrial dysfunction, and increases in the population of sub-G1 hypodiploid cells and apoptotic cells, caspase-3 activity, and the activation of caspase cascades. Etoposide also increased the phosphorylation levels of glycogen synthase kinase (GSK)-3α/β in treated RIN-m5F cells. Pretreatment with LiCl, a GSK-3 inhibitor, prevented etoposide-induced mitochondria-dependent apoptosis and GSK-3 protein phosphorylation in RIN-m5F cells. Furthermore, exposure of the cells to etoposide induced the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-related kinase (ERK)1/2 but not p38-MAPK, which was suppressed by the specific JNK inhibitor (SP600125) and ERK1/2 inhibitor (PD98059), respectively. Additionally, pretreatment with both SP600125 and PD98059 effectively suppressed etoposide-induced β-cell cytotoxicity, apoptosis, and GSK-3 protein phosphorylation; however, LiCl did not reverse JNK and ERK1/2 phosphorylation. Taken together, these results suggest that etoposide is capable of causing cytotoxicity on pancreatic β-cells by inducing apoptosis through the JNK/ERK-mediated GSK-3 downstream-triggered mitochondria-dependent signaling pathway.
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: Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, Taichung 404, Taiwan; Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua County 500, 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: Division of Toxicology, Trauma & Emergency Center, China Medical University Hospital, Taichung 404, Taiwan.
authors.forename: Dong-Zong
authors.initials: DZ
authors.lastname: Hung
authors.affiliation: School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan.
authors.forename: Ching-Ting
authors.initials: CT
authors.lastname: Lin
authors.affiliation: Department of Physiology, and Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, Taichung 404, Taiwan.
authors.forename: Tien-Hui
authors.initials: TH
authors.lastname: Lu
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan. Electronic address: shinghwaliu@ntu.edu.tw.
authors.forename: Shing-Hwa
authors.initials: SH
authors.lastname: Liu
authors.affiliation: School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan; Department of Nursing, College of Medical and Health Science, Asia University, Taichung 413, Taiwan. Electronic address: cfhuang@mail.cmu.edu.tw.
authors.forename: Chun-Fa
authors.initials: CF
authors.lastname: Huang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005047:Etoposide / Q000633:toxicity*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3
keywords: Apoptosis; Etoposide; GSK-3; JNK/ERK; Mitochondria; Pancreatic β-cells