title: Hydrophobic statins induce autophagy and cell death in human rhabdomyosarcoma cells by depleting geranylgeranyl diphosphate.
abstract: Statins are the most common type of medicine used to treat hypercholesterolemia; however, they are associated with a low incidence of myotoxicity such as myopathy and rhabdomyolysis. The mechanisms for the adverse effects remain to be fully elucidated for safer chronic use and drug development. The results of our earlier work suggested that hydrophobic statins induce autophagy in cultured human rhabdomyosarcoma A204 cells. In this study, we first confirmed the statin-induced autophagy by assessing other criteria, including induced expression of the autophagy-related genes, enhanced protein degradation of autophagy marker protein p62 and electron microscopic observation of induced formation of autophagosome. We next demonstrated that the extent of inhibition of HMG-CoA reductase in the cell is parallel with the ability of a statin to induce autophagy. Thus, the primary activity of statins causes autophagy in A204 cells. Considering the mechanism for the induction, we showed that statins induce autophagy by depleting cellular levels of geranylgeranyl diphosphate (GGPP) mostly through an unknown pathway that does not involve two major small G proteins, Rheb and Ras. Finally, we demonstrated that the ability of statins to induce autophagy parallels their toxicity to A204 cells and that both can be suppressed by GGPP.
authors.affiliation: Department of Biochemistry, Meiji Pharmaceutical University, Kiyose, Tokyo 204-8588, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Araki
authors.forename: Masatomo
authors.initials: M
authors.lastname: Maeda
authors.forename: Kiyoto
authors.initials: K
authors.lastname: Motojima
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins / Q000037:antagonists & inhibitors; D009479:Neuropeptides / Q000037:antagonists & inhibitors; D011106:Polyisoprenyl Phosphates / Q000378:metabolism*; D000076205:Ras Homolog Enriched in Brain Protein; D012208:Rhabdomyosarcoma / Q000473:pathology*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D011106:Polyisoprenyl Phosphates; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; D020559:Monomeric GTP-Binding Proteins; C002963:geranylgeranyl pyrophosphate