The von Hippel-Lindau tumor suppressor protein sensitizes renal cell carcinoma cells to tumor necrosis factor-induced cytotoxicity by suppressing the nuclear factor-kappaB-dependent antiapoptotic pathway.

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.

• Authors: Heng Qi, Michael Ohh
• Journal: Cancer research (Cancer Res) Vol. 63 Issue 21 Pg. 7076-80 (Nov 01 2003) ISSN: 0008-5472 [Print] United States
• PMID: 14612498 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BIRC5 protein, human
• CASP8 and FADD-Like Apoptosis Regulating Protein
• CFLAR protein, human
• Carrier Proteins
• Caspase Inhibitors
• Inhibitor of Apoptosis Proteins
• Intracellular Signaling Peptides and Proteins
• Microtubule-Associated Proteins
• NF-kappa B
• Neoplasm Proteins
• Proteins
• Survivin
• Tumor Necrosis Factor-alpha
• Tumor Suppressor Proteins
• Ubiquitin-Protein Ligases
• Von Hippel-Lindau Tumor Suppressor Protein
• CASP3 protein, human
• CASP8 protein, human
• CASP9 protein, human
• Caspase 3
• Caspase 8
• Caspase 9
• Caspases
• VHL protein, human

Topics

• Apoptosis (drug effects, genetics, physiology)
• CASP8 and FADD-Like Apoptosis Regulating Protein
• Carcinoma, Renal Cell (drug therapy, metabolism, pathology)
• Carrier Proteins (antagonists & inhibitors, biosynthesis, genetics)
• Caspase 3
• Caspase 8
• Caspase 9
• Caspase Inhibitors
• Caspases (biosynthesis, genetics, metabolism)
• Cell Nucleus (metabolism)
• Enzyme Induction
• Gene Expression Regulation, Neoplastic (drug effects, physiology)
• Humans
• Inhibitor of Apoptosis Proteins
• Intracellular Signaling Peptides and Proteins
• Kidney Neoplasms (drug therapy, metabolism, pathology)
• Microtubule-Associated Proteins (antagonists & inhibitors, biosynthesis, genetics)
• NF-kappa B (antagonists & inhibitors, metabolism)
• Neoplasm Proteins
• Protein Biosynthesis
• Proteins (antagonists & inhibitors, genetics)
• Survivin
• Tumor Necrosis Factor-alpha (pharmacology)
• Tumor Suppressor Proteins (physiology)
• Ubiquitin-Protein Ligases (physiology)
• Von Hippel-Lindau Tumor Suppressor Protein