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Statins are effective cholesterol-lowering drugs that exert pleiotropiceffects, including cytotoxicity to cancer cells. We previously reported that simvastatintriggered the mitochondrial apoptotic pathway in MethA fibrosarcoma cells, whichwas accompanied by the translocation of stabilized p53 to the mitochondria. Inthis study, we investigated whether statins induce the endoplasmic reticulum (ER)stress response and the mechanisms by which this response is linked to the stabilizationof p53 and its translocation to the mitochondria. Statins induced typical ER stress-relatedproteins, such as BiP/78 kDa glucose-regulated protein (Grp78) and CCAAT/enhancer-bindingprotein homologous protein (CHOP), as well as the phosphorylation of protein kinaseRNA-like endoplasmic reticulum kinase (PERK), eIF2α and JNK. The statin-inducedphosphorylation of eIF2α and JNK was inhibited by supplementation with componentsof the mevalonate pathway, such as mevalonate, farnesyl pyrophosphate (FPP) andgeranylgeranyl pyrophosphate (GGPP). Salubrinal, an inhibitor of the dephosphorylationof eIF2α, suppressed the loss of mitochondrial membrane potential and the translocationof stabilized p53 and Bax to the mitochondria; however, SP600125, a JNK kinaseinhibitor, did not exert this effect. Furthermore, the eIF2α knockdown sensitizedcells to simvastatin-induced apoptosis and the overexpression of a non-phosphorylatableeIF2α-mutant [serine 51(Ser51)/alanine] enhanced the stabilization of p53 andits translocation to the mitochondria in response to simvastatin treatment. Takentogether, these data indicate that eIF2α phosphorylation in the context of theER stress response plays a role in cell survival by counteracting the p53-mediatedmitochondrial apoptosis in response to statins.

Phosphorylation of eIF2α attenuates statin-induced apoptosis by inhibiting the stabilization and translocation of p53 to the mitochondria