| Renal cell carcinoma (RCC) is a highly aggressive cancer, which, unfortunately, has limited treatment options once it has metastasized. However, research within the last few years has demonstrated the effectiveness of a new class of drugs in treating RCC. These drugs, potent inhibitors of the protein mammalian target of rapamycin (mTOR), have proven to be the most effective therapeutics to date in treating RCC.;In this dissertation, the inhibitory effects of two agents, the 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) and the drug 5-aminoimidazole-4-carboxamide riboside (AICAR), in RCC are explored. 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. AICAR is a potent pharmacological activator of AMP-activated kinase (AMPK), a cellular energy sensor that negatively regulates the mTOR signaling pathway. As mTOR plays critical roles in cell growth and tumorigenesis of RCC cells, we examined the effects of statins and/or AICAR on regulation of mTOR activity and growth and survival of such cells.;Experimental findings identified statins as potent novel inhibitors of the Akt/mTOR signaling pathway in RCC. Statins and AICAR each induced apoptosis in RCC cells and also had potent inhibitory effects on RCC cell growth. Interestingly, concomitant treatments of cells with combinations of statins and AICAR had potent additive/synergistic effects in RCC cells. Experimental findings demonstrated that overexpression of Akt rescued the apoptotic effects of statins in these cells as well as rescued the apoptotic effects induced by dual treatment with statins and AICAR, indicating the position of Akt upstream of AMPK in mediating cellular response to these agents. Also, similar suppressive growth effects were obtained when statins were combined with a different AMPK activator, metformin.;Altogether these data establish that statins and/or AMPK activators exhibit potent anti-RCC activities via inhibitory effects on the Akt/mTOR pathway. Interestingly, statins and AMPK activators also exhibited anti-tumor effects in melanoma, further validating the possibility that these agents may be of future therapeutic value in the treatment of RCC as well as other solid tumors. |
