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

Cancer Res. 2003 Nov 1;63(21):7076-80.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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