Lovastatin Induces Apoptosis of Anaplastic Thyroid Cancer Cells via Inhibition of Protein Geranylgeranylation and de Novo Protein Synthesis

Abstract

Lovastatin has been used to treat hypercholesterolemia through blocking the mevalonate biosynthesis pathway. Inhibition of mevalonate synthesis may result in antiproliferation and cell apoptosis. The aim of the present study was to examine the apoptotic effect of lovastatin in human ARO cells and delineate its underlying molecular mechanism. Our results showed that lovastatin dose- and time-dependently induced apoptosis in ARO cells. Pretreatment with cycloheximide 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 microM lovastatin induced cytochrome c translocation from mitochondria to cytosol; increases in caspase-2, -3, and -9 activity; and poly (ADP-ribose) polymerase degradation in a time-dependent manner. However, administration of mevalonate or geranylgeraniol, but not farnesol, dose-dependently prevented lovastatin-induced poly (ADP-ribose) polymerase degradation and the occurrence of apoptosis, but treatment with geranylgeranyl transferase 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 lovastatin dose-dependently decreased the translocation of RhoA and Rac1, but not Ras, from cytosol to membrane fraction. Moreover, the lovastatin-induced translocation inhibitions in RhoA and Rac1 were prevented by mevalonate and geranylgeraniol but not farnesol. 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.

Determinants of sensitivity to lovastatin-induced apoptosis in multiple myeloma

“…As isopentenyl PPi is also depleted by statin exposure, it would be unavailable to the statin-treated cell (49,50). These results, as well as the ability of GGTI-298 to induce apoptosis comparably with statins in sensitive tumor lines, build on previous reports (1,11,16,41) to clearly indicate the importance of protein geranylgeranylation in statininduced apoptosis.…”

“…We and others have shown that of these downstream end-products, GGPP most consistently reverses statin-induced apoptosis in sensitive tumor cells (1,11,16,41). To evaluate the mechanism of lovastatininduced apoptosis in MM, four sensitive MM cell lines (KMS11, OPM2, H929 and OCI MY7) were screened by 3-4,5-dimethylthiazolyl-2,2,5-diphenyl tetrazolium bromide assay, as we have previously conducted (41).…”

“…The Rho GTPases are isoprenylated proteins differentially expressed in response to lovastatin within sensitive MM cells, and have previously been implicated in statin-induced apoptosis in tumor cells, including MM (4,11,18). Together, these data prompted us to assess whether members of this family could functionally modulate sensitivity to lovastatin-induced apoptosis in MM cells.…”

The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion–mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase

“…This is in concordance with the observation in thyroid cancer that Rho protein is the pivotal element for cellular survival, whereas farnesylation of Ras proteins was not involved. 30,31 Interestingly, the isoprenylated proteins did not influence the cytomorphology of the cells, 30 because RhoA has been implicated in changes of cell morphology, formation of stress fibers, and focal adhesion. 48,49 The roles of Rho protein and Rho kinase in multiple myeloma are poorly understood.…”

Rho kinase in the regulation of cell death and survival

“…Rho/ROCK activation also plays a pro-survival role during oxidative stress (H 2 O 2 )-induced intestinal epithelial cell injury via activation of PKCδ and PKD [129]. In anaplastic thyroid cancer cells, inhibition of Rho by lovastatin or inhibition of ROCK by Y27632 induces cytochrome c release, activation of caspases 3 and 9, and apoptosis which required de novo protein synthesis [154]. Inhibition of Rho or ROCK results in activation of caspases 3, 8 and 9, and glioma cell apoptosis [110].…”