title: Mevalonate depletion mediates the suppressive impact of geranylgeraniol on murine B16 melanoma cells.
abstract: The diterpene geranylgeraniol (all trans-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen-1-ol) suppresses the growth of human liver, lung, ovary, pancreas, colon, stomach and blood tumors with undefined mechanisms. We evaluated the growth-suppressive activity of geranylgeraniol in murine B16 melanoma cells. Geranylgeraniol induced dose-dependent suppression of B16 cell growth (IC(50) = 55 ± 13 µmol/L) following a 48-h incubation in 96-well plates. Cell cycle arrest at the G1 phase, manifested by a geranylgeraniol-induced increase in the G1/S ratio and decreased expression of cyclin D1 and cyclin-dependent kinase 4, apoptosis detected by Guava Nexin™ assay and fluorescence microscopy following acridine orange and ethidium bromide dual staining, and cell differentiation shown by increased alkaline phosphatase activity, contributed to the growth suppression. Murine 3T3-L1 fibroblasts were 10-fold more resistant than B16 cells to geranylgeraniol-mediated growth suppression. Geranylgeraniol at near IC(50) concentration (60 µmol/L) suppressed the mRNA level of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase by 50%. The impact of geranylgeraniol on B16 cell growth, cell cycle arrest and apoptosis were attenuated by supplemental mevalonate, the product of HMG-CoA reductase that is essential for cell growth. Geranylgeraniol and d-δ-tocotrienol, a down-regulator of HMG-CoA reductase, additively suppressed the growth of B16 cells. These results support our hypothesis that mevalonate depletion mediates the tumor-specific growth-suppressive impact of geranylgeraniol. Geranylgeraniol may have potential in cancer chemoprevention and/or therapy.
authors.affiliation: Department of Nutrition and Food Sciences, Texas Woman’s University, Denton, 76204, USA.
authors.forename: Rajasekhar
authors.initials: R
authors.lastname: Katuru
authors.forename: Nicolle V
authors.initials: NV
authors.lastname: Fernandes
authors.forename: Manal
authors.initials: M
authors.lastname: Elfakhani
authors.forename: Dibyendu
authors.initials: D
authors.lastname: Dutta
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Mills
authors.forename: DiAnna L
authors.initials: DL
authors.lastname: Hynds
authors.forename: Clay
authors.initials: C
authors.lastname: King
authors.forename: Huanbiao
authors.initials: H
authors.lastname: Mo
mesh_terms: D041721:3T3-L1 Cells; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000201:enzymology / Q000473:pathology*; D008798:Mevalonic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D051379:Mice; D014810:Vitamin E / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D004224:Diterpenes; D019938:Cyclin D1; D014810:Vitamin E; C082097:tocotrienol, delta; C015367:mevalonolactone; D008148:Lovastatin; C017338:geranylgeraniol; D051358:Cyclin-Dependent Kinase 4; D000469:Alkaline Phosphatase; D008798:Mevalonic Acid