Synergistic induction of apoptosis by HMG-CoA reductase inhibitor and histone deacetylases inhibitor in HeLa cells

• Published in: Biochemical and biophysical research communications Vol. 365; no. 2; pp. 386 - 392
• Main Authors: Gan, Yehua, Wang, Jian, Coselli, Joseph, Wang, Xing Li
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.01.2008
• Subjects: Acyl Coenzyme A - metabolism; Apoptosis; Apoptosis - drug effects; Dose-Response Relationship, Drug; HeLa Cells; Histone Deacetylase Inhibitors; Histone Deacetylases - metabolism; HMG-CoA; Humans; Hydroxamic Acids - administration & dosage; Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage; Lovastatin - administration & dosage; Lovastatin - analogs & derivatives; RhoA; Statin; TSA; HMG-CoA; TSA; Statin; RhoA; Apoptosis
• DOI: 10.1016/j.bbrc.2007.11.002
• ISSN: 0006-291X

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) β subunit expression, which is one of the key enzymes for protein geranylgeranylation. Taken together, TSA down-regulated GGTase-I β expression, hence enhanced the statin-induced depletion of geranylgeranylated RhoA, which could be an important mechanism for the synergistic induction of the apoptosis.