title: Lovastatin induces apoptosis of k-ras-transformed thyroid cells via inhibition of ras farnesylation and by modulating redox state.
abstract: Transformation of thyroid cells with either K-ras or H-ras viral oncogenes produces cell types with different phenotype and different response to the inhibition of the prenylation pathway by 3-hydroxy-3-methylglutaryl-CoA reductase or farnesyltransferase inhibitors. These inhibitors induce apoptosis in K-ras-transformed FRTL-5 cells (FRTL-5-K-Ras) whereas cell cycle arrest is induced in H-ras-transformed FRTL-5 (FRTL-5-H-Ras). In FRTL-5-K-Ras cells, the product of K-ras gene is implicated in the scavenging of reactive oxygen species (ROS) through the activation of extracellular-signal-regulated kinase (ERK)1/2 kinases. We observed that lovastatin blocked ras activation through inhibition of farnesylation and induced apoptosis, increasing ROS levels through inhibition of ERK1/2 signaling and Mn-SOD expression. Lovastatin-induced apoptosis was due to intracellular ROS increase since both, the antioxidant compound pyrrolidinedithiocarbamate or the SOD-mimetic compound, antagonized apoptosis. Moreover, both p38 mitogen-activated protein kinase and nuclear factor kappaB pathways, activated as a consequence of high ROS levels, are involved in the apoptotic effect, indicating that cell death induced by lovastatin was dependent on oxidative stress. Lovastatin antitumor efficacy in K-ras-dependent thyroid tumors was further confirmed in vivo, proposing a new therapeutic strategy for those tumor diseases that are sustained by an inappropriate K-ras expression.
authors.affiliation: IEOS, CNR, Naples, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Laezza
authors.forename: Laura
authors.initials: L
authors.lastname: Fiorentino
authors.forename: Simona
authors.initials: S
authors.lastname: Pisanti
authors.forename: Patrizia
authors.initials: P
authors.lastname: Gazzerro
authors.forename: Michele
authors.initials: M
authors.lastname: Caraglia
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Portella
authors.forename: Mario
authors.initials: M
authors.lastname: Vitale
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bifulco
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D005260:Female; D011905:Genes, ras; D008148:Lovastatin / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D054876:Prenylation; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013961:Thyroid Gland / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D008148:Lovastatin
references.citation: Nat Rev Cancer. 2003 Jan;3(1):11-22
references.pmid: 12509763
references.citation: Brain Res Bull. 2004 Feb 15;62(6):497-504
references.pmid: 15036564
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13646-51
references.pmid: 9811854
references.citation: Nat Rev Cancer. 2006 Apr;6(4):292-306
references.pmid: 16557281
references.citation: Int J Cancer. 1981 Nov 15;28(5):655-62
references.pmid: 6273340
references.citation: J Biol Chem. 1998 Feb 6;273(6):3285-90
references.pmid: 9452444
references.citation: Endocrinology. 2007 Nov;148(11):5186-94
references.pmid: 17690162
references.citation: Cancer Res. 2004 May 15;64(10):3580-5
references.pmid: 15150115
references.citation: Mol Cancer Ther. 2007 Jun;6(6):1886-97
references.pmid: 17575117
references.citation: Endocrinology. 1999 Feb;140(2):698-704
references.pmid: 9927296
references.citation: J Biol Chem. 1999 Oct 8;274(41):29294-302
references.pmid: 10506188
references.citation: J Biol Chem. 2004 May 21;279(21):22138-44
references.pmid: 15037631
references.citation: Mol Cell Biol. 1983 Nov;3(11):2099-109
references.pmid: 6318081
references.citation: Carcinogenesis. 2003 Mar;24(3):453-9
references.pmid: 12663504
references.citation: Cancer Res. 2007 Sep 15;67(18):8762-71
references.pmid: 17875717
references.citation: Clin Cancer Res. 1999 Aug;5(8):2223-9
references.pmid: 10473109
references.citation: Endocr Relat Cancer. 2005 Sep;12(3):615-29
references.pmid: 16172195
references.citation: Proc Natl Acad Sci U S A. 1989 Nov;86(21):8323-7
references.pmid: 2682646
references.citation: J Cell Physiol. 2002 Jul;192(1):1-15
references.pmid: 12115731
references.citation: Exp Biol Med (Maywood). 2007 Apr;232(4):523-31
references.pmid: 17392488
references.citation: J Neurochem. 2007 Nov;103(4):1472-80
references.pmid: 17680990
references.citation: Endocr Relat Cancer. 2006 Mar;13(1):7-26
references.pmid: 16601276
references.citation: Int J Cancer. 2006 Feb 1;118(3):773-9
references.pmid: 16094629
references.citation: Biochimie. 1999 Apr;81(4):287-90
references.pmid: 10401660
references.citation: Cancer Cell. 2007 Feb;11(2):191-205
references.pmid: 17292829
references.citation: Biochem Biophys Res Commun. 2007 Apr 13;355(3):807-12
references.pmid: 17316570
references.citation: Trends Biochem Sci. 1996 Dec;21(12):488-91
references.pmid: 9009833
references.citation: Cell. 1989 Jun 30;57(7):1167-77
references.pmid: 2661017
references.citation: FEBS Lett. 1995 Jan 16;358(1):1-3
references.pmid: 7821417
references.citation: J Virol. 1985 Oct;56(1):284-92
references.pmid: 2993656
references.citation: Trends Mol Med. 2004 Nov;10(11):549-57
references.pmid: 15519281
references.citation: Oncogene. 1999 Nov 22;18(49):6910-24
references.pmid: 10602466
references.citation: Cell Death Differ. 2001 Feb;8(2):144-51
references.pmid: 11313716
references.citation: Curr Drug Targets. 2005 May;6(3):301-23
references.pmid: 15857290
references.citation: Cancer Res. 1991 Feb 1;51(3):794-8
references.pmid: 1846317
references.citation: FEBS Lett. 2005 Jun 6;579(14):3029-36
references.pmid: 15896789
references.citation: Science. 1987 Oct 23;238(4826):542-5
references.pmid: 2821624
references.citation: Curr Biol. 2001 Apr 17;11(8):614-9
references.pmid: 11369207