Synergistic induction of apoptosis by HMG-CoA reductase inhibitor and histone deacetylases inhibitor in HeLa cells.
HMG-CoA reductase inhibitors and histone deacetylases (HDACs) inhibitors have been shown to induce apoptosis in a variety of cells, which could potentially be used as an anticancer therapy in addition to the designated applications. In the present study, we explored the possible synergistic pro-apoptotic effects and the underlying mechanisms when the two classes of inhibitors were combined. Exposure of HeLa cells to the combined treatment of mevastatin (an inhibitor of HMG-CoA reductase) and trichostatin A (TSA) (an inhibitor of HDACs) synergistically induced apoptosis. Mevastatin treatment transcriptionally and translationally up-regulated RhoA expression in the cells by negative feedback mechanism. While TSA enhanced mevastatin-induced RhoA up-regulation, more importantly, it also accelerated mevastatin-mediated depletion of membrane-bound (geranylgeranylated) RhoA. Moreover, TSA treatment down-regulated protein geranylgeranyl transferase-I (GGTase-I) beta subunit expression, which is one of the key enzymes for protein geranylgeranylation. Taken together, TSA down-regulated GGTase-I beta expression, hence enhanced the statin-induced depletion of geranylgeranylated RhoA, which could be an important mechanism for the synergistic induction of the apoptosis.
Gan
Yehua
Y
Laboratory of Molecular Biology and Center for TMJ Disorders, Peking University School and Hospital of Stomatology, 22 Zhongguancun Nandajie, Beijing 100081, PR China. kqyehuagan@bjmu.edu.cn
Wang
Jian
J
Coselli
Joseph
J
Wang
Xing Li
XL
D000214:Acyl Coenzyme A / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D008148:Lovastatin / Q000008:administration & dosage / Q000031:analogs & derivatives*
D000214:Acyl Coenzyme A; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; C012258:mevastatin; C012589:trichostatin A; D008148:Lovastatin; D006655:Histone Deacetylases