2. Academic Validation
  3. Etoposide induces pancreatic β-cells cytotoxicity via the JNK/ERK/GSK-3 signaling-mediated mitochondria-dependent apoptosis pathway

Etoposide induces pancreatic β-cells cytotoxicity via the JNK/ERK/GSK-3 signaling-mediated mitochondria-dependent apoptosis pathway

  • Toxicol In Vitro. 2016 Oct;36:142-152. doi: 10.1016/j.tiv.2016.07.018.
Kuan-I Lee 1,  Chin-Chuan Su 2,  Ching-Yao Yang 3,  Dong-Zong Hung 4,  Ching-Ting Lin 5,  Tien-Hui Lu 6,  Shing-Hwa Liu 7,  Chun-Fa Huang 8
Affiliations

Affiliations

  • 1 Department of Emergency, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, Taiwan.
  • 2 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.
  • 3 Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan; Department of Surgery, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
  • 4 Division of Toxicology, Trauma & Emergency Center, China Medical University Hospital, Taichung 404, Taiwan.
  • 5 School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan.
  • 6 Department of Physiology, and Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, Taichung 404, Taiwan.
  • 7 Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan. Electronic address: shinghwaliu@ntu.edu.tw.
  • 8 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.
PMID: 27473919 DOI: 10.1016/j.tiv.2016.07.018
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.

Keywords

Apoptosis; Etoposide; GSK-3; JNK/ERK; Mitochondria; Pancreatic β-cells.

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