geranylgeranyl-pyrophosphate and Uterine-Cervical-Neoplasms

Aberrant activation of GTPases is common in cervical cancer, and their proper biological functions largely depend on a post-translational modification termed prenylation. Simvastatin is a cholesterol-lowering drug via inhibiting HMG-CoA reductase, thereby inhibiting protein prenylation. In this study, we show that simvastatin selectively inhibits proliferation and induces apoptosis in cervical cancer cells while sparing normal cervical epithelial cells. This is achieved by depleting geranylgeranyl pyrophosphate, inhibiting prenylation, decreasing GTPases activities and suppressing the activation of downstream Ras and RhoA signaling. The combination of simvastatin and paclitaxel remarkably augments in vitro as well as in vivo efficacy of either drug alone in cellular system and xenograft mouse model. Importantly, we show that cervical cancer cells have higher level of HMG-CoA reductase and elevated activities of GTPases, suggesting that cervical cancer cells may be more dependent on prenylation than normal cervical epithelial cells. This might explain the selective inhibitory effects of simvastatin in cervical cancer. Since simvastatin is already available for clinic use, these results suggest that simvastatin is a promising drug candidate in combination with chemotherapy for the treatment of cervical cancer. Our findings also emphasize the therapeutic value of prenylation inhibition and provide preclinical evidence to evaluate prenylation-targeted drugs in cervical cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Cell Proliferation; Female; GTP Phosphohydrolases; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice, SCID; Paclitaxel; Polyisoprenyl Phosphates; Protein Prenylation; Simvastatin; Uterine Cervical Neoplasms; Xenograft Model Antitumor Assays

Recent reports have suggested that statins induce cell death in certain epithelial cancers and that patients taking statins to reduce cholesterol levels possess lower cancer incidence. However, little is known about the mechanisms of action of different statins or the effects of these statins in gynaecological malignancies. The apoptotic potential of two lipophilic statins (lovastatin and simvastatin) and one hydrophilic statin (pravastatin) was assessed in cancer cell lines (ovarian, endometrial and cervical) and primary cultured cancerous and normal tissues. Cell viability was studied by MTS assays and apoptosis was confirmed by Western blotting of PARP and flow cytometry. The expressions of key apoptotic cascade proteins were analysed. Our results demonstrate that both lovastatin and simvastatin, but not pravastatin, selectively induced cell death in dose- and time-dependent manner in ovarian, endometrial and cervical cancers. Little or no toxicity was observed with any statin on normal cells. Lipophilic statins induced activation of caspase-8 and -9; BID cleavage, cytochrome C release and PARP cleavage. Statin-sensitive cancers expressed high levels of HMG-CoA reductase compared with resistant cultures. The effect of lipophilic statins was dependent on inhibition of enzymatic activity of HMG-CoA reductase since mevalonate pre-incubation almost completely abrogated the apoptotic effect. Moreover, the apoptotic effect involved the inhibition of synthesis of geranylgeranyl pyrophosphate rather than farnesyl pyrophosphate. In conclusion, lipophilic but not hydrophilic statins induce cell death through activation of extrinsic and intrinsic apoptotic cascades in cancerous cells from the human female genital tract, which express high levels of HMG-CoA reductase. These results promote further investigation in the use of lipophilic statins as anticancer agents in gynaecological malignancies.

Topics: Cell Death; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Drug Synergism; Epithelium; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Genital Neoplasms, Female; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Lovastatin; Mevalonic Acid; Ovarian Neoplasms; Polyisoprenyl Phosphates; Pravastatin; Sesquiterpenes; Signal Transduction; Simvastatin; Uterine Cervical Neoplasms; Water