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

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Abstract
In renal cell carcinomas (RCC), NF-κB blockade is required for maximal bortezomib-induced apoptosis, and expression of the von Hippel-Lindau (VHL) tumor suppressor protein downregulates NF-κB. Thus, we hypothesized that expression of wild-type (wt) VHL sensitizes RCC cells to bortezomib by reducing constitutive NF-κB activity. Using isogenic paired cell lines with and without expression of wtVHL, we have confirmed that VHL expression reduces constitutive NF-κB 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-κB 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-κB 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.