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

摘要: Purpose: Statins are pharmacologic inhibitors of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase with potent regulatory effects on cholesterol biosynthesis in vitro and vivo . There is accumulating evidence that, beyond their cholesterol-lowering properties, statins inhibit cell proliferation promote apoptosis malignant cells , but mechanisms by which they generate such responses remain to be defined. Experimental Design: Combinations experimental approaches were used, including immunoblotting assays. Results: We provide that fluvastatin a inducer suppresses renal carcinoma (RCC) Such mediated direct targeting Akt/mammalian target rapamycin (mTOR) pathway, as evidenced suppression phosphorylation/activation Akt, resulting inhibition its downstream effectors, mTOR p70 S6 kinase. In addition, blocks mTOR-dependent phosphorylation/deactivation translational repressor eukaryotic initiation factor 4E (eIF4E)-binding protein, leading formation eIF4E-binding protein-eIF4E complexes suppress cap-dependent mRNA translation. Importantly, kinase activity results up-regulation expression programmed death 4 (PDCD4), tumor suppressor protein inhibitory translation eIF4A, suggesting mechanism for generation antitumor responses. Conclusions: Altogether, our findings establish exhibits anti-RCC activities via Akt/mTOR pathway raise possibility combinations Akt may future therapeutic value treatment RCC.