VHL expression in renal cell carcinoma sensitizes to bortezomib (PS-341) through an NF-kappaB-dependent mechanism.
In renal cell carcinomas (RCC), NF-kappaB blockade is required for maximal bortezomib-induced apoptosis, and expression of the von Hippel-Lindau (VHL) tumor suppressor protein downregulates NF-kappaB. Thus, we hypothesized that expression of wild-type (wt) VHL sensitizes RCC cells to bortezomib by reducing constitutive NF-kappaB activity. Using isogenic paired cell lines with and without expression of wtVHL, we have confirmed that VHL expression reduces constitutive NF-kappaB activity. Moreover, VHL expression confers markedly heightened sensitivity to the growth inhibitory effects of bortezomib in vitro. The bortezomib IC50 values were greater than two logs lower in the VHL-expressing cell lines compared to the VHL-deficient counterparts. By manipulating the level of constitutive NF-kappaB activity in an isogenic pair of RCC cell lines independently of VHL expression, we were able to demonstrate that the VHL sensitization effect is due to downregulation of NF-kappaB activity. These findings offer the enticing possibility of using VHL status as a molecular marker to identify RCC patients who may be sensitive to bortezomib. In particular, RCC patients who have non-clear-cell histologies as well as approximately 25% of clear-cell RCCs manifest expression of wtVHL and represent a subpopulation of patients that is apt to respond to bortezomib.
An
Jiabin
J
VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA.
Fisher
Myrna
M
Rettig
Matthew B
MB
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D017239:Paclitaxel / Q000627:therapeutic use; D011719:Pyrazines / Q000627:therapeutic use*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D006623:von Hippel-Lindau Disease / Q000235:genetics
D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; D025521:Tumor Suppressor Proteins; D000069286:Bortezomib; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human; D017239:Paclitaxel