| Summary: | 博士 === 國立臺灣大學 === 生理學研究所 === 92 === Lovastatin has been used to treat hyperlipidemia through blocking the mevalonate biosynthesis pathway. Inhibition of mevalonate synthesis may result in anti-proliferation and cell apoptosis. The aim of the present study was to examine the apoptotic effect of lovastatin in human ARO cells and to delineate its molecular mechanism underlying. Using DNA fragmentation and flow cytometry analyses, we demonstrated that lovastatin induced the occurrence of apoptosis in ARO cells in a dose- and time-dependent manner. Pretreatment of ARO cells with cycloheximide (CHX) dose-dependently suppressed lovastatin-induced apoptosis, suggesting that de novo protein synthesis is required for lovastatin effect on the induction of apoptosis in ARO cells. Treatment of the cells with 50 mM lovastatin induced cytochrome c translocation from mitochondria to cytosol, increases in caspases 2, 3 and 9 activity, and poly (ADP-ribose) polymerase (PARP) degradation in a time-dependent manner. However, administration of mevalonate or geranylgeraniol (GGOH), but not farnesol (FOH), dose-dependently prevented lovastatin-induced PARP degradation and the occurrence of apoptosis, while treatment of ARO cells with geranylgeranyltransferase (GGTase) inhibitor, GGTI-298, which blocks the geranylgeranylation, induced an increase in the percentage of the apoptotic cells. These data suggest that geranylgeranylation is required for survival of the lovastatin-treated ARO cells. To support this notion, we demonstrate that treatment of the cells with lovastatin dose-dependently decreased the translocation of RhoA and Rac1, but not Ras, from cytosol to membrane fraction. Moreover, the inhibitions of lovastatin-induced membrane translocation in RhoA and Rac1 were prevented by mevalonate and GGOH, but not by FOH. In conclusion, our data suggest that lovastatin induced apoptosis in ARO cells by inhibiting protein geranylgeranylation of the Rho family, but not farnesylation of the Ras family.
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