Received for publication December 1, 2005.
Revised March 1, 2006.
Accepted for publication March 16, 2006.

Induction of apoptosis in renal cell carcinoma by reactive oxygen species: involvement of ERK1/2, p38/, COX-2 downregulation and AIF translocation

Abstract

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 guanosine 3'5'-monophosphate 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 employed both genetic and pharmacological approaches. LY83583 induced a time- and dose-dependent increase in RCC apoptosis through dephosphorylation of MEK1/2 and its downstream kinases ERK1 and -2. In addition we observed a decrease in Elk-1 phosphorylation and COX-2 downregulation. Surprisingly, we failed to observe an increase in either c-Jun NH2-terminal kinase or p38 and MAPK activation. Paradoxically, 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-xL and Bax expression, respectively, as well as cytochrome c release and AIF translocation. 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 as well as COX-2 downregulation, and apoptosis. In conclusion, our results suggest that LY83583 may represent a novel therapeutic agent for the treatment of RCCs which remain highly refractory to antineoplastic agents. Our data provide a molecular basis for the anticancer activity of LY83583.

Key words: MAP Kinase, Jun Kinase, P38 MAP Kinase, Apoptosis, Oxidative stress/antioxidants, Reactive intermediates, Overexpression, Mechanisms of cell killing/apoptosis

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