Statin-dependent suppression of the Akt/mammalian target of rapamycin signaling cascade and programmed cell death 4 up-regulation in renal cell carcinoma.
OBJECTIVE
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.


METHODS
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.
Woodard
Jennifer
J
Robert H. Lurie Comprehensive Cancer Center , Northwestern University Medical School, Chicago, Illinois, USA.
Sassano
Antonella
A
Hay
Nissim
N
Platanias
Leonidas C
LC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects* / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015151:Immunoblotting; D007680:Kidney Neoplasms / Q000378:metabolism*; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C114487:PDCD4 protein, human; D016601:RNA-Binding Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases