PMID- 18779944
OWN - NLM
STAT- MEDLINE
DCOM- 20090326
LR  - 20211020
IS  - 0946-2716 (Print)
IS  - 0946-2716 (Linking)
VI  - 86
IP  - 12
DP  - 2008 Dec
TI  - Lovastatin induces apoptosis of k-ras-transformed thyroid cells via inhibition of 
      ras farnesylation and by modulating redox state.
PG  - 1341-51
LID - 10.1007/s00109-008-0396-1 [doi]
AB  - 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.
FAU - Laezza, Chiara
AU  - Laezza C
AD  - IEOS, CNR, Naples, Italy.
FAU - Fiorentino, Laura
AU  - Fiorentino L
FAU - Pisanti, Simona
AU  - Pisanti S
FAU - Gazzerro, Patrizia
AU  - Gazzerro P
FAU - Caraglia, Michele
AU  - Caraglia M
FAU - Portella, Giuseppe
AU  - Portella G
FAU - Vitale, Mario
AU  - Vitale M
FAU - Bifulco, Maurizio
AU  - Bifulco M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080909
PL  - Germany
TA  - J Mol Med (Berl)
JT  - Journal of molecular medicine (Berlin, Germany)
JID - 9504370
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Reactive Oxygen Species)
RN  - 9LHU78OQFD (Lovastatin)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/metabolism/*pharmacology
MH  - Apoptosis
MH  - Cell Cycle/drug effects
MH  - Cell Line
MH  - Cell Transformation, Neoplastic
MH  - Female
MH  - Genes, ras
MH  - Lovastatin/metabolism/*pharmacology
MH  - Male
MH  - Mice
MH  - Mice, Nude
MH  - Prenylation
MH  - Rats
MH  - Reactive Oxygen Species/metabolism
MH  - Signal Transduction/drug effects
MH  - Thyroid Gland/*cytology/*drug effects/metabolism
EDAT- 2008/09/10 09:00
MHDA- 2009/03/27 09:00
CRDT- 2008/09/10 09:00
PHST- 2008/02/04 00:00 [received]
PHST- 2008/08/04 00:00 [accepted]
PHST- 2008/08/01 00:00 [revised]
PHST- 2008/09/10 09:00 [pubmed]
PHST- 2009/03/27 09:00 [medline]
PHST- 2008/09/10 09:00 [entrez]
AID - 10.1007/s00109-008-0396-1 [doi]
PST - ppublish
SO  - J Mol Med (Berl). 2008 Dec;86(12):1341-51. doi: 10.1007/s00109-008-0396-1. Epub 
      2008 Sep 9.