Abstract
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)-kappaB in the nuclear fraction capable of binding NF-kappaB-binding motifs was significantly increased in RC3 cells. Concordantly, the expression of NF-kappaB-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-kappaB activity and subsequent attenuation of antiapoptotic proteins c-FLIP, Survivin, c-IAP-1, and c-IAP-2.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects*
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Apoptosis / genetics
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Apoptosis / physiology
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Carcinoma, Renal Cell / drug therapy*
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Carcinoma, Renal Cell / metabolism*
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Carcinoma, Renal Cell / pathology
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / biosynthesis
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Carrier Proteins / genetics
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Caspase 3
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Caspase 8
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Caspase 9
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Caspase Inhibitors
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Caspases / biosynthesis
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Caspases / genetics
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Caspases / metabolism
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Cell Nucleus / metabolism
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Enzyme Induction
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / physiology
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Humans
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Inhibitor of Apoptosis Proteins
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Intracellular Signaling Peptides and Proteins*
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Kidney Neoplasms / drug therapy*
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Kidney Neoplasms / metabolism*
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Kidney Neoplasms / pathology
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Microtubule-Associated Proteins / antagonists & inhibitors
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Microtubule-Associated Proteins / biosynthesis
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Microtubule-Associated Proteins / genetics
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NF-kappa B / antagonists & inhibitors*
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NF-kappa B / metabolism
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Neoplasm Proteins
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Protein Biosynthesis
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Proteins / antagonists & inhibitors
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Proteins / genetics
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Survivin
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Tumor Necrosis Factor-alpha / pharmacology*
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Tumor Suppressor Proteins / physiology*
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Ubiquitin-Protein Ligases / physiology*
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Von Hippel-Lindau Tumor Suppressor Protein
Substances
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BIRC5 protein, human
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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Carrier Proteins
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Caspase Inhibitors
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Inhibitor of Apoptosis Proteins
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Intracellular Signaling Peptides and Proteins
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Microtubule-Associated Proteins
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NF-kappa B
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Neoplasm Proteins
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Proteins
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Survivin
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Tumor Necrosis Factor-alpha
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Tumor Suppressor Proteins
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Ubiquitin-Protein Ligases
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Von Hippel-Lindau Tumor Suppressor Protein
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CASP3 protein, human
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CASP8 protein, human
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CASP9 protein, human
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Caspase 3
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Caspase 8
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Caspase 9
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Caspases
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VHL protein, human