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

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 (elF4E)-binding protein, leading to the formation of elF4E-binding protein-elF4E 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 elF4A, 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.