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Statin-Dependent Suppression of the Akt/Mammalian Target of Rapamycin Signaling Cascade and Programmed Cell Death 4 Up-Regulation in Renal Cell Carcinoma

Authors' Affiliations: ¹ Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School and Lakeside Veterans Affairs Medical Center, and ² Department of Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois

Requests for reprints: Leonidas C. Platanias, Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School and Lakeside Veterans Affairs Medical Center, 303 East Superior Street, Lurie 3-107, Chicago, IL 60611. Phone: 312-503-4267; Fax: 312-908-1372; E-mail: l-platanias{at}northwestern.edu.

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.