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
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DOI：
10.1016/j.tiv.2016.07.018
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发表时间：
2016-10-01
影响因子：
3.2
通讯作者：
Huang, Chun-Fa
中科院分区：
文献类型：
--
作者：
Lee, Kuan-I;Su, Chin-Chuan;Huang, Chun-Fa
依托泊苷广泛用于治疗不同类型的肿瘤，如胰腺癌。然而，依托泊苷也在正常活细胞（包括胰腺β细胞）中引起一些不希望的副作用，这些细胞易受化学诱导的损伤，并且依托泊苷诱导的细胞凋亡的分子机制仍然不清楚。在此，结果表明，在RIN-m5 F细胞（一种β细胞衍生的细胞系）中，依托泊苷处理24小时后活细胞的数量显著减少，并经历线粒体依赖性凋亡信号，伴随线粒体功能障碍，亚G1亚二倍体细胞和凋亡细胞的数量增加，半胱天冬酶-3活性增加，半胱天冬酶级联激活。依托泊苷还增加了经处理的RIN-m5 F细胞中糖原合成酶激酶（GSK）-3 α/β的磷酸化水平。GSK-3抑制剂LiCl预处理可抑制依托泊苷诱导的RIN-m5 F细胞凋亡和GSK-3蛋白磷酸化。此外，暴露于依托泊苷诱导c-jun N-末端激酶（JNK）和细胞外信号相关激酶（ERK）1/2的磷酸化，但不p38-MAPK，这是由特异性JNK抑制剂（SP 600125）和ERK 1/2抑制剂（PD 98059）分别抑制。此外，用SP 600125和PD 98059预处理有效地抑制了依托泊苷诱导的β细胞毒性、凋亡和GSK-3蛋白磷酸化;然而，LiCl没有逆转JNK和ERK 1/2磷酸化。综上所述，这些结果表明，依托泊苷能够通过JNK/ERK介导的GSK-3下游触发的ERK依赖性信号通路诱导细胞凋亡，从而对胰腺β细胞产生细胞毒性。(C)2016爱思唯尔有限公司版权所有
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 beta-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 beta-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)-3 alpha/beta in treated RIN-m5F cells. Pretreatment with LiCI, 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 (INK) 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 beta-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 beta-cells by inducing apoptosis through the JNK/ERK-mediated GSK-3 downstream-triggered mitochondria-dependent signaling pathway. (C) 2016 Elsevier Ltd. All rights reserved.