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 farnesly and geranylgeranly 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 micromol/L) and mevastatin (1-10 micromol/L). Supplementation of cultures with geranylgeranyl pyrophosphates (100 micromol/L) was observed to rescue drug-induced phenotypic changes whereas farnesyl pyrophosphate (100 micromol/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.
Department of Orthopaedics - The Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA.
Valentine B
VB
Andela
Michael
M
Pirri
Edward M
EM
Schwarz
Edward J
EJ
Puzas
Regis J
RJ
O'Keefe
Joseph D
JD
Rosenblatt
Randy N
RN
Rosier
D000209:Acute-Phase Proteins / Q000502:physiology; D019386:Alendronate / Q000494:pharmacology*; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D051231:Farnesyltranstransferase; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D011106:Polyisoprenyl Phosphates / Q000032:analysis; D014407:Tumor Cells, Cultured
D000209:Acute-Phase Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; C010781:acute-phase protein rho; C012258:mevastatin; D008148:Lovastatin; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid; D019386:Alendronate