http://www.cnr.it/ontology/cnr/individuo/prodotto/ID21096
Lovastatin induces apoptosis of k-ras-transformed thyroid cells via inhibition of ras farnesylation and by modulating redox state. (Articolo in rivista)
- Type
- Label
- Lovastatin induces apoptosis of k-ras-transformed thyroid cells via inhibition of ras farnesylation and by modulating redox state. (Articolo in rivista) (literal)
- Anno
- 2008-01-01T00:00:00+01:00 (literal)
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- Laezza C; Fiorentino L; Pisanti S; Gazzerro P; Caraglia M; Portella G; Vitale M; Bifulco M (literal)
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- ISI Web of Science (WOS) (literal)
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- Univ Salerno, Dept Pharmaceut Sci, I-84084 Salerno, Italy
CNR, IEOS, I-80125 Naples, Italy
Univ Naples Federico 2, Dept Cellular & Mol Biol & Pathol L Califano, Naples, Italy
Natl Inst Tumours Fdn G Pascale Naples, Expt Pharmacol Unit, Naples, Italy
Univ Naples Federico 2, Dept Mol & Clin Endocrinol & Oncol, Naples, Italy (literal)
- Titolo
- Lovastatin induces apoptosis of k-ras-transformed thyroid cells via inhibition of ras farnesylation and by modulating redox state. (literal)
- 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 kappa B 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. (literal)
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