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Etoposide induces pancreatic β-cells cytotoxicity via the JNK/ERK/GSK-3 signaling-mediated mitochondria-dependent apoptosis pathway.
- Source :
-
Toxicology in Vitro . Oct2016, Vol. 36, p142-152. 11p. - Publication Year :
- 2016
-
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 24 h 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 08872333
- Volume :
- 36
- Database :
- Academic Search Index
- Journal :
- Toxicology in Vitro
- Publication Type :
- Academic Journal
- Accession number :
- 117800895
- Full Text :
- https://doi.org/10.1016/j.tiv.2016.07.018