This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Qi, H. Articles by Ohh, M. Search for Related Content PubMed PubMed Citation Articles by Qi, H. Articles by Ohh, M.

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.

This article has been cited by other articles:

				S. A.J. VAZIRI, D. R. GRABOWSKI, J. HILL, L. R. RYBICKI, R. BURK, R. M. BUKOWSKI, M. K. GANAPATHI, and R. GANAPATHI Inhibition of Proteasome Activity by Bortezomib in Renal Cancer Cells Is p53 Dependent and VHL Independent Anticancer Res, August 1, 2009; 29(8): 2961 - 2969. [Abstract] [Full Text] [PDF]

				S. Mahajan, V. Dammai, T. Hsu, and A.S. Kraft Hypoxia-inducible factor-2{alpha} regulates the expression of TRAIL receptor DR5 in renal cancer cells Carcinogenesis, September 1, 2008; 29(9): 1734 - 1741. [Abstract] [Full Text] [PDF]

				C. Sourbier, S. Danilin, V. Lindner, J. Steger, S. Rothhut, N. Meyer, D. Jacqmin, J.-J. Helwig, H. Lang, and T. Massfelder Targeting the Nuclear Factor-{kappa}B Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy Cancer Res., December 15, 2007; 67(24): 11668 - 11676. [Abstract] [Full Text] [PDF]

				G. Raval, S. Biswas, P. Rayman, K. Biswas, G. Sa, S. Ghosh, M. Thornton, C. Hilston, T. Das, R. Bukowski, et al. TNF-{alpha} Induction of GM2 Expression on Renal Cell Carcinomas Promotes T Cell Dysfunction J. Immunol., May 15, 2007; 178(10): 6642 - 6652. [Abstract] [Full Text] [PDF]

				W. G. Kaelin Jr. The von Hippel-Lindau Tumor Suppressor Protein and Clear Cell Renal Carcinoma Clin. Cancer Res., January 15, 2007; 13(2): 680s - 684s. [Abstract] [Full Text] [PDF]

				J. An and M. B. Rettig Epidermal growth factor receptor inhibition sensitizes renal cell carcinoma cells to the cytotoxic effects of bortezomib Mol. Cancer Ther., January 1, 2007; 6(1): 61 - 69. [Abstract] [Full Text] [PDF]

				E. P. Cummins, E. Berra, K. M. Comerford, A. Ginouves, K. T. Fitzgerald, F. Seeballuck, C. Godson, J. E. Nielsen, P. Moynagh, J. Pouyssegur, et al. Prolyl hydroxylase-1 negatively regulates I{kappa}B kinase-beta, giving insight into hypoxia-induced NF{kappa}B activity PNAS, November 28, 2006; 103(48): 18154 - 18159. [Abstract] [Full Text] [PDF]

				E. Nakamura, P. Abreu-e-Lima, Y. Awakura, T. Inoue, T. Kamoto, O. Ogawa, H. Kotani, T. Manabe, G.-J. Zhang, K. Kondo, et al. Clusterin Is a Secreted Marker for a Hypoxia-Inducible Factor-Independent Function of the von Hippel-Lindau Tumor Suppressor Protein Am. J. Pathol., February 1, 2006; 168(2): 574 - 584. [Abstract] [Full Text] [PDF]

				J. An and M. B. Rettig Mechanism of von Hippel-Lindau Protein-Mediated Suppression of Nuclear Factor kappa B Activity Mol. Cell. Biol., September 1, 2005; 25(17): 7546 - 7556. [Abstract] [Full Text] [PDF]

				F. Kosari, A. S. Parker, D. M. Kube, C. M. Lohse, B. C. Leibovich, M. L. Blute, J. C. Cheville, and G. Vasmatzis Clear Cell Renal Cell Carcinoma: Gene Expression Analyses Identify a Potential Signature for Tumor Aggressiveness Clin. Cancer Res., July 15, 2005; 11(14): 5128 - 5139. [Abstract] [Full Text] [PDF]

				M.-T. Lin, C.-C. Chang, S.-T. Chen, H.-L. Chang, J.-L. Su, Y.-P. Chau, and M.-L. Kuo Cyr61 Expression Confers Resistance to Apoptosis in Breast Cancer MCF-7 Cells by a Mechanism of NF-{kappa}B-dependent XIAP Up-Regulation J. Biol. Chem., June 4, 2004; 279(23): 24015 - 24023. [Abstract] [Full Text] [PDF]