Suppression of the proliferation of Ras-transformed cells by fluoromevalonate, an inhibitor of mevalonate metabolism.
Mevalonate is the precursor of a number of different products potentially required for the growth of cells, including the prenylated oncoprotein Ras. To determine whether inhibition of mevalonate metabolism would selectively block proliferation of Ras-transformed cells, 6-fluoromevalonate (Fmev), an inhibitor of diphosphomevalonate decarboxylase, was used to block the synthesis of prenyl-derived lipids and prenylated proteins in interleukin-3 (IL-3)-dependent FDC-P1 cells (control FDC-P1 cells) and FDC-P1 cells transformed with oncogenic Ras (RasDC cells) that proliferated in the absence of IL-3. Fmev completely inhibited synthesis of prenyl-derived lipids and prenylated proteins and blocked proliferation of FDC-P1 and RasDC cells. Restoration of the proliferation of Fmev-blocked FDC-P1 cells required both an exogenous source of cholesterol and prevention of the accumulation of mevalonate and the mevalonate phosphates with lovastatin. In contrast, ongoing IL-3-independent proliferation of Fmev-blocked RasDC cells was not completely restored by providing exogenous cholesterol and preventing the accumulation of inhibitory mevalonate product(s). However, these cells proliferated when cultures were supplemented with IL-3 together with exogenous cholesterol and lovastatin, implying that Fmev had prevented Ras-dependent, IL-3-independent growth. Fmev markedly diminished total cellular Ras in RasDC cells. In contrast, lovastatin depleted membrane-associated Ras and increased cytosolic Ras but did not diminish total cellular Ras. These data indicate that Fmev depletes total cellular Ras and specifically inhibits the autonomous growth of Ras-transformed cells.
Cuthbert
J A
JA
Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas 75235-8887, USA.
Lipsky
P E
PE
D000818:Animals; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors; D002455:Cell Division / Q000187:drug effects*; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D002784:Cholesterol / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects; D011905:Genes, ras; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D007700:Kinetics; D008798:Mevalonic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms
D007377:Interleukin-3; D011994:Recombinant Proteins; C045174:6-fluoromevalonolactone; D002784:Cholesterol; D002262:Carboxy-Lyases; C022503:pyrophosphomevalonate decarboxylase; D008798:Mevalonic Acid