Cadmium exposure induces pancreatic β-cell death via a Ca2+-triggered JNK/CHOP-related apoptotic signaling pathway
Cadmium exposure induces pancreatic β-cell death via a Ca2+-triggered JNK/CHOP-related apoptotic signaling pathway
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DOI：
10.1016/j.tox.2019.152252
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发表时间：
2019-09-01
期刊：
影响因子：
4.5
通讯作者：
Huang, Chun-Fa
中科院分区：
文献类型：
--
作者：
Huang, Cheng-Chin;Kuo, Chun-Ying;Huang, Chun-Fa
镉（Cd）被有毒物质和疾病登记署列为物质优先级列表中的第7位有害物质。实验和流行病学数据表明，镉与糖尿病（DM）的发展有关。镉对胰腺β细胞毒性的分子机制尚不清楚。有证据表明，Ca 2+是毒性胰岛素诱导的β细胞毒性的重要调节剂。Ca ~（2+）在Cd诱导的β细胞毒性中的作用尚不清楚。在这项研究中，我们发现，镉暴露显着抑制胰岛素分泌和胰腺β细胞衍生的RIN-m5 F细胞的细胞活力。镉暴露可诱导细胞凋亡，包括凋亡细胞和亚G1期亚二倍体细胞数量的增加，以及caspase-3/-7/-9和多聚腺苷二磷酸核糖聚合酶（PARP）的激活，这在很大程度上依赖于c-Jun N-末端激酶（JNK）和C/EBP同源蛋白（CHOP）的激活。用JNK和CHOP的siRNA转染或用JNK的特异性药理学抑制剂（SP 600125）预处理β细胞有效地防止了Cd诱导的胰岛素分泌功能障碍和细胞凋亡。JNK特异性siRNA显著抑制镉诱导的JNK磷酸化和CHOP蛋白表达，但JNK磷酸化不能被CHOP特异性siRNA抑制。此外，镉暴露显着增加细胞内钙（[Ca 2 +]（i））水平。用BAPTA/AM缓冲Ca 2+反应有效地消除了Cd诱导的[Ca 2 +]（i）升高、胰岛素分泌功能障碍、细胞凋亡以及JNK磷酸化和CHOP激活的蛋白表达。综上所述，这些发现表明，镉暴露通过[Ca 2 +]（i）依赖性JNK激活激活下游CHOP相关凋亡信号通路引起β细胞死亡。
Cadmium (Cd) is known to be ranked the 7th hazardous substance in the Substance Priority List by Agency for Toxic Substances and Disease Registry. The experimental and epidemiological data have suggested that Cd is linked to the development of diabetes mellitus (DM). The molecular mechanism of Cd on the pancreatic beta-cell cytotoxicity still remains unclear. Evidence has pointed toward that Ca2+ is an important regulator of toxic insult-induced beta-cell cytotoxicity. The role of Ca2+ in the Cd-induced beta-cell cytotoxicity is still unknown. In this study, we found that Cd exposure significantly inhibited insulin secretion and cell viability in the pancreatic beta-cell-derived RIN-m5F cells. Cd exposure induced apoptotic events, including the increased populations of apoptotic cells and sub-G1 hypodiploid cells, and caspase-3/-7/-9 and poly (ADP-ribose) polymerase (PARP) activation, which largely depended on the activation of c-Jun N-terminal kinase (JNK) and C/EBP homologous protein (CHOP). Transfection with siRNAs for JNK and CHOP or pretreatment with specific pharmacological inhibitor of JNK (SP600125) in beta-cells effectively prevented the Cd-induced insulin secretion dysfunction and apoptosis. JNK-specific siRNA dramatically suppressed Cd-induced JNK phosphorylation and CHOP protein expression, but JNK phosphorylation could not be inhibited by CHOP-specific siRNA. Furthermore, Cd exposure significantly increased the intracellular calcium ([Ca2+](i)) levels. Buffering the Ca2+ response with BAPTA/AM effectively abrogated the Cd-induced [Ca2+](i) elevation, insulin secretion dysfunction, apoptosis, and protein expression of JNK phosphorylation and CHOP activation. Taken together, these findings demonstrated that Cd exposure exerts beta-cell death via a [Ca2+](i)-dependent JNK activation-activated downstream CHOP-related apoptotic signaling pathway.