Phosphorylation of eIF2α attenuates statin-induced apoptosis by inhibiting             the stabilization and translocation of p53 to the mitochondria.
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.
Department of Biochemistry, College of Natural Sciences, Chungnam National University,                     Daejeon 305-764, Republic of Korea.
Sang Kyu
SK
Lee
Young Sang
YS
Kim
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D000924:Anticholesteremic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D005354:Fibrosarcoma; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008798:Mevalonic Acid / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering; D012717:Sesquiterpenes / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
D000873:Anthracenes; D000924:Anticholesteremic Agents; D002934:Cinnamates; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; D008798:Mevalonic Acid; D011106:Polyisoprenyl Phosphates; D034741:RNA, Small Interfering; D012717:Sesquiterpenes; D019821:Simvastatin; D013890:Thiourea; D051742:Transcription Factor CHOP; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D019892:eIF-2 Kinase; C497250:Ddit3 protein, mouse; C000717248:Hspa5 protein, mouse; C496827:salubrinal; C432165:pyrazolanthrone; C004808:farnesyl pyrophosphate; C002963:geranylgeranyl pyrophosphate