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The von Hippel-Lindau Tumor Suppressor Protein Sensitizes Renal Cell Carcinoma Cells to Tumor Necrosis Factor-Induced Cytotoxicity By Suppressing the Nuclear Factor-B-Dependent Antiapoptotic Pathway¹

Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, M5S 1A8 Canada

Functional inactivation of the von Hippel-Lindau (VHL) tumor suppressor protein pVHL is the cause of the familial VHL disease and the majority of sporadic renal clear cell carcinomas (RCCs). RCCs pose a significant problem for conventional cancer treatment protocols because of their highly recalcitrant characteristics to radio- and/or chemotherapies. In fact, the leading cause of morbidity and mortality of VHL patients is RCC. Recently, global gene profiling of RCC cells has revealed that sensitivity to tumor necrosis factor (TNF)--mediated cytotoxicity is pVHL dependent. Here, we report that although RCC cells devoid of functional pVHL (RC3) were resistant to the cytotoxic effects of TNF-, reconstitution of these RCC cells with wild-type pVHL (WT8) restored their sensitivity to TNF- cytotoxicity. The major TNF--inducible transcription factor nuclear factor (NF)-B in the nuclear fraction capable of binding NF-B-binding motifs was significantly increased in RC3 cells. Concordantly, the expression of NF-B-target antiapoptotic genes c-FLIP, Survivin, c-IAP-1, and cIAP-2, which block the activities of caspases 8 and 3, were dramatically elevated in RC3 cells. Indeed, RC3 cells showed low caspases 8 and 3 activities. These results demonstrate that pVHL facilitates TNF--induced cytotoxicity in RCC cells, at least in part, through the down-regulation of NF-B activity and subsequent attenuation of antiapoptotic proteins c-FLIP, Survivin, c-IAP-1, and c-IAP-2.

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