Lovastatin induces apoptosis of k-ras-transformed thyroid cells via inhibition of ras farnesylation and by modulating redox state.
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.
Laezza
Chiara
C
IEOS, CNR, Naples, Italy.
Fiorentino
Laura
L
Pisanti
Simona
S
Gazzerro
Patrizia
P
Caraglia
Michele
M
Portella
Giuseppe
G
Vitale
Mario
M
Bifulco
Maurizio
M
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
D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D008148:Lovastatin
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