PMID- 18628479
OWN - NLM
STAT- MEDLINE
DCOM- 20080916
LR  - 20211203
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 14
IP  - 14
DP  - 2008 Jul 15
TI  - Statin-dependent suppression of the Akt/mammalian target of rapamycin signaling 
      cascade and programmed cell death 4 up-regulation in renal cell carcinoma.
PG  - 4640-9
LID - 10.1158/1078-0432.CCR-07-5232 [doi]
AB  - PURPOSE: Statins are pharmacologic inhibitors of the 
      3-hydroxy-3-methylglutaryl-coenzyme A reductase with potent regulatory effects on 
      cholesterol biosynthesis in vitro and in vivo. There is accumulating evidence 
      that, beyond their cholesterol-lowering properties, statins inhibit cell 
      proliferation and promote apoptosis of malignant cells in vitro, but the 
      mechanisms by which they generate such responses remain to be defined. 
      EXPERIMENTAL DESIGN: Combinations of experimental approaches were used, including 
      immunoblotting and cell proliferation and apoptosis assays. RESULTS: We provide 
      evidence that fluvastatin is a potent inducer of apoptosis and suppresses 
      proliferation of renal cell carcinoma (RCC) cells in vitro. Such effects are 
      mediated by direct targeting of the Akt/mammalian target of rapamycin (mTOR) 
      pathway, as evidenced by the suppression of phosphorylation/activation of Akt, 
      resulting in inhibition of its downstream effectors, mTOR and p70 S6 kinase. In 
      addition, fluvastatin blocks the mTOR-dependent phosphorylation/deactivation of 
      the translational repressor eukaryotic initiation factor 4E (eIF4E)-binding 
      protein, leading to the formation of eIF4E-binding protein-eIF4E complexes that 
      suppress initiation of cap-dependent mRNA translation. Importantly, inhibition of 
      p70 S6 kinase activity by fluvastatin results in the up-regulation of expression 
      of programmed cell death 4 (PDCD4), a tumor suppressor protein with inhibitory 
      effects on the translation initiation factor eIF4A, suggesting a mechanism for 
      the generation of antitumor responses. CONCLUSIONS: Altogether, our findings 
      establish that fluvastatin exhibits potent anti-RCC activities via inhibitory 
      effects on the Akt/mTOR pathway and raise the possibility that combinations of 
      statins and Akt inhibitors may be of future therapeutic value in the treatment of 
      RCC.
FAU - Woodard, Jennifer
AU  - Woodard J
AD  - Robert H. Lurie Comprehensive Cancer Center , Northwestern University Medical 
      School, Chicago, Illinois, USA.
FAU - Sassano, Antonella
AU  - Sassano A
FAU - Hay, Nissim
AU  - Hay N
FAU - Platanias, Leonidas C
AU  - Platanias LC
LA  - eng
GR  - CA100579/CA/NCI NIH HHS/United States
GR  - CA121192/CA/NCI NIH HHS/United States
GR  - CA77816/CA/NCI NIH HHS/United States
GR  - T32CA009560/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 0 (PDCD4 protein, human)
RN  - 0 (RNA-Binding Proteins)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Apoptosis Regulatory Proteins/*drug effects/metabolism
MH  - Carcinoma, Renal Cell/*metabolism
MH  - Cell Line, Tumor
MH  - Electrophoresis, Polyacrylamide Gel
MH  - Flow Cytometry
MH  - Humans
MH  - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology
MH  - Immunoblotting
MH  - Kidney Neoplasms/*metabolism
MH  - Protein Kinases/*drug effects/metabolism
MH  - Proto-Oncogene Proteins c-akt/*drug effects/metabolism
MH  - RNA-Binding Proteins/*drug effects/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/drug effects/physiology
MH  - TOR Serine-Threonine Kinases
MH  - Up-Regulation
EDAT- 2008/07/17 09:00
MHDA- 2008/09/17 09:00
CRDT- 2008/07/17 09:00
PHST- 2008/07/17 09:00 [pubmed]
PHST- 2008/09/17 09:00 [medline]
PHST- 2008/07/17 09:00 [entrez]
AID - 14/14/4640 [pii]
AID - 10.1158/1078-0432.CCR-07-5232 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2008 Jul 15;14(14):4640-9. doi: 10.1158/1078-0432.CCR-07-5232.