The Mevalonate Synthesis Pathway as a Therapeutic Target in Cancer

Farnesyl transferase inhibitors have emerged as bona fide anticancer agents whereas the development of geranylgeranyl transferase inhibitors has been mitigated by overt systemic toxicities. Evidence suggests that the therapeutic value of farnesyl transferase inhibitors is an indirect result of perturbations in the function of geranylgeranylated Rho proteins. To address this question, we used inhibitors of the mevalonate synthesis pathway to decrease cellular levels of farnesyl and geranylgeranyl isoprenoids and supplemented our culture systems with exogenous isoprenoids accordingly. Using a murine lung alveolar carcinoma cell line (Line 1), we report a dose-dependent inhibition of tumor cell proliferation, adhesion and invasiveness, in response to alendronate (3-30 μmol/L) and mevastatin (1-10 μmol/L). Supplementation of cultures with geranylgeranyl pyrophosphates (100 μmol/L) was observed to rescue drug-induced phenotypic changes whereas farnesyl pyrophosphate (100 μmol/L) had a minimal effect. Our observations highlight the mevalonate synthesis pathway as a target for anticancer therapies and suggest a greater role for geranylgeranylated proteins in cellular processes germane to cancer.