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Induction of Apoptosis in Renal Cell Carcinoma by Reactive Oxygen Species: Involvement of Extracellular Signal-Regulated Kinase 1/2, p38/, Cyclooxygenase-2 Down-Regulation, and Translocation of Apoptosis-Inducing Factor

Departments of Pharmacology and Therapeutics (M.A., O.P.B.), Medicine (A.R.), and Cork Cancer Research Center, Leslie C. Quick, Jr., Cancer Laboratory Bioscience Institute and Mercy University Hospital (G.C.O.S., C.D., O.P.B.), National University of Ireland, Cork, Ireland

Renal cell carcinoma (RCC) is the most common malignancy of the kidney. Unfortunately, RCCs are highly refractory to conventional chemotherapy, radiation therapy, and even immunotherapy. Thus, novel therapeutic targets need to be sought for the successful treatment of RCCs. We now report that 6-anilino-5,8-quinolinequinone (LY83583), an inhibitor of cyclic GMP production, induced growth arrest and apoptosis of the RCC cell line 786-0. It did not prove deleterious to normal renal epithelial cells, an important aspect of chemotherapy. To address the cellular mechanism(s), we used both genetic and pharmacological approaches. LY83583 induced a time- and dose-dependent increase in RCC apoptosis through dephosphorylation of mitogen-activated protein kinase kinase 1/2 and its downstream extracellular signal-regulated kinases (ERK) 1 and -2. In addition, we observed a decrease in Elk-1 phosphorylation and cyclooxygenase-2 (COX-2) down-regulation. We were surprised that we failed to observe an increase in either c-Jun NH₂-terminal kinase or p38 and - mitogen-activated protein kinase activation. In contradiction, reintroduction of p38 by stable transfection or overexpression of p38 dominant negative abrogated the apoptotic effect. Cell death was associated with a decrease and increase in Bcl-x_L and Bax expression, respectively, as well as release of cytochrome c and translocation of apoptosis-inducing factor. These events were associated with an increase in reactive oxygen species formation. The antioxidant N-acetyl L-cysteine, however, opposed LY83583-mediated mitochondrial dysfunction, ERK1/2 inactivation, COX-2 down-regulation, and apoptosis. In conclusion, our results suggest that LY83583 may represent a novel therapeutic agent for the treatment of RCC, which remains highly refractory to antineoplastic agents. Our data provide a molecular basis for the anticancer activity of LY83583.

Address correspondence to: Orla P. Barry, Department of Pharmacology and Therapeutics, Clinical Science Building, Cork University Hospital, Cork, Ireland. E-mail: o.barry{at}ucc.ie

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