Phosphorylation of eIF2α attenuates statin-induced apoptosis by inhibiting the stabilization and translocation of p53 to the mitochondria.
Phosphorylation of eIF2α attenuates statin-induced apoptosis by inhibiting the stabilization and translocation of p53 to the mitochondria.
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DOI：
10.3892/ijo.2013.1792
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发表时间：
2013-03
影响因子：
5.2
通讯作者：
Kim YS
中科院分区：
文献类型：
--
作者：
Lee SK;Kim YS
他汀类药物是有效的降胆固醇药物，具有多效作用，包括对癌细胞的细胞毒性。我们以前报道，辛伐他汀触发线粒体凋亡途径在MethA纤维肉瘤细胞，这是伴随着稳定的p53易位到线粒体。在这项研究中，我们研究了他汀类药物是否诱导内质网（ER）应激反应，以及这种反应与p53稳定及其向线粒体转运有关的机制。他汀类药物可诱导典型的内质网应激相关蛋白，如BiP/78 kDa葡萄糖调节蛋白（Grp 78）和CCAAT/增强子结合蛋白同源蛋白（CHOP），以及蛋白激酶RNA样内质网激酶（PERK）、eIF 2 α和JNK的磷酸化。补充甲羟戊酸途径的组分，如甲羟戊酸、焦磷酸法呢酯（FPP）和焦磷酸香叶基香叶基酯（GGPP），可抑制他汀类药物诱导的eIF 2 α和JNK磷酸化。Salubrinal是eIF 2 α去磷酸化的抑制剂，抑制线粒体膜电位的丧失和稳定的p53和Bax向线粒体的移位;然而，SP 600125，JNK激酶抑制剂，没有发挥这种作用。此外，eIF 2 α敲低使细胞对辛伐他汀诱导的细胞凋亡敏感，并且不可磷酸化的eIF 2 α突变体[丝氨酸51（Ser 51）/丙氨酸]的过表达增强了p53的稳定性及其在辛伐他汀处理后向线粒体的转运。总之，这些数据表明，在ER应激反应的背景下，eIF 2 α磷酸化通过抵消p53介导的线粒体凋亡对他汀类药物的反应在细胞存活中起作用。
Statins are effective cholesterol-lowering drugs that exert pleiotropic effects, including cytotoxicity to cancer cells. We previously reported that simvastatin triggered the mitochondrial apoptotic pathway in MethA fibrosarcoma cells, which was accompanied by the translocation of stabilized p53 to the mitochondria. In this study, we investigated whether statins induce the endoplasmic reticulum (ER) stress response and the mechanisms by which this response is linked to the stabilization of p53 and its translocation to the mitochondria. Statins induced typical ER stress-related proteins, such as BiP/78 kDa glucose-regulated protein (Grp78) and CCAAT/ enhancer-binding protein homologous protein (CHOP), as well as the phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK), eIF2α and JNK. The statin-induced phosphorylation of eIF2α and JNK was inhibited by supplementation with components of the mevalonate pathway, such as mevalonate, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Salubrinal, an inhibitor of the dephosphorylation of eIF2α, suppressed the loss of mitochondrial membrane potential and the translocation of stabilized p53 and Bax to the mitochondria; however, SP600125, a JNK kinase inhibitor, did not exert this effect. Furthermore, the eIF2α knockdown sensitized cells to simvastatin-induced apoptosis and the overexpression of a non-phosphorylatable eIF2α-mutant [serine 51(Ser51)/alanine] enhanced the stabilization of p53 and its translocation to the mitochondria in response to simvastatin treatment. Taken together, these data indicate that eIF2α phosphorylation in the context of the ER stress response plays a role in cell survival by counteracting the p53-mediated mitochondrial apoptosis in response to statins.
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