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

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)- alpha -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- alpha , reconstitution of these RCC cells with wild-type pVHL (WT8) restored their sensitivity to TNF- alpha cytotoxicity. The major TNF- alpha -inducible transcription factor nuclear factor (NF)- Kappa B in the nuclear fraction capable of binding NF- Kappa B-binding motifs was significantly increased in RC3 cells. Concordantly, the expression of NF- Kappa 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- alpha -induced cytotoxicity in RCC cells, at least in part, through the down-regulation of NF- Kappa B activity and subsequent attenuation of antiapoptotic proteins c-FLIP, Survivin, c-IAP-1, and c-IAP-2.