title: Lovastatin and perillyl alcohol inhibit glioma cell invasion, migration, and proliferation--impact of Ras-/Rho-prenylation.
abstract: Alterations in small GTPase mediated signal transduction pathways have emerged as a central step in the molecular pathogenesis of glioblastoma (GBM), the most common malignant brain tumor in adults. Farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) are derived from mevalonate, whose production is catalyzed by 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Prenylation by FPP and GGPP is required for membrane insertion and oncogenic function of Ras- and Rho-proteins, within the stimulation of the Ras-Raf-MEK-ERK pathway. A straightforward prediction from HMG-CoA reductase inhibitor studies is that statins decrease FPP and GGPP levels and diminish ERK signaling ensuring less proliferation and migration of cancer cells. Perillyl alcohol (POH), a naturally occurring monoterpene inhibits prenyltransferases and is able to inhibit cancer cell growth, but the underlying mechanism is still unclear. We here report that lovastatin (LOV) and POH impair the regulation of the mevalonate- and the Ras-Raf-MEK-ERK pathway in U87 and U343 glioblastoma cells. Both compounds affected the post-translational modification of H-Ras and Rac1. While LOV diminished the substrates of the transferase reaction that catalyze prenylation, POH inhibited the enzymes itself. Our data highlight the impact of isoprenoids for post-translational modification of small GTPases promoting proliferation, migration and invasion capabilities in glioma cells.
authors.affiliation: Department of Pharmacology, Goethe-University, Frankfurt, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Afshordel
authors.affiliation: Department of Pharmacology, Goethe-University, Frankfurt, Germany.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Kern
authors.affiliation: Department of Pharmacology, Goethe-University, Frankfurt, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Clasohm
authors.affiliation: Division of Experimental Neurosurgery, University Clinics of Frankfurt, Germany.
authors.forename: Hildegard
authors.initials: H
authors.lastname: König
authors.affiliation: Division of Experimental Neurosurgery, University Clinics of Frankfurt, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Priester
authors.affiliation: Division of Experimental Neurosurgery, University Clinics of Frankfurt, Germany.
authors.forename: Jakob
authors.initials: J
authors.lastname: Weissenberger
authors.affiliation: Division of Experimental Neurosurgery, University Clinics of Frankfurt, Germany.
authors.forename: Donat
authors.initials: D
authors.lastname: Kögel
authors.affiliation: Department of Pharmacology, Goethe-University, Frankfurt, Germany. Electronic address: G.P.Eckert@em.uni-frankfurt.de.
authors.forename: Gunter P
authors.initials: GP
authors.lastname: Eckert
mesh_terms: D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology*; D039821:Monoterpenes / Q000494:pharmacology*; D009361:Neoplasm Invasiveness; D054876:Prenylation; D013729:Terpenes / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D039821:Monoterpenes; D013729:Terpenes; C032208:perillyl alcohol; D002784:Cholesterol; D008148:Lovastatin; D020830:rac1 GTP-Binding Protein; D018631:ras Proteins
keywords: ERK pathway; Glioblastoma; Perillyl alcohol; Protein prenylation; Statin