VHL expression in renal cell carcinoma sensitizes to bortezomib (PS-341) through an NF-κB-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.