geranylgeranyl-pyrophosphate and salubrinal

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.

Topics: Animals; Anthracenes; Anticholesteremic Agents; Apoptosis; bcl-2-Associated X Protein; Cell Line, Tumor; Cell Survival; Cinnamates; eIF-2 Kinase; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2; Fibrosarcoma; Heat-Shock Proteins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; JNK Mitogen-Activated Protein Kinases; Membrane Potential, Mitochondrial; Mevalonic Acid; Mice; Mitochondria; Phosphorylation; Polyisoprenyl Phosphates; Protein Transport; RNA Interference; RNA, Small Interfering; Sesquiterpenes; Signal Transduction; Simvastatin; Thiourea; Transcription Factor CHOP; Tumor Suppressor Protein p53