Maximal apoptosis of renal cell carcinoma by the proteasome inhibitor bortezomib is nuclear factor-kappaB dependent.

Advanced renal cell carcinoma (RCC) is resistant to cytotoxic chemotherapy, and immunotherapy has modest activity. Proteasome inhibitors represent a novel class of anticancer agents that have activity across a wide spectrum of tumor types. We investigated the efficacy of the proteasome inhibitor bortezomib (VELCADE, formerly known as PS-341) in RCC and found that bortezomib potently induces apoptosis of RCC cell lines. Blockade of the nuclear factor-kappaB (NF-kappaB) pathway is considered a crucial effect in bortezomib-induced apoptosis, but the dependence on NF-kappaB inhibition for bortezomib-mediated death has not been formally demonstrated. Thus, we also studied the contribution of NF-kappaB inhibition as a mechanism of bortezomib-induced apoptosis in RCC cells, which display constitutive NF-kappaB activation. Ectopic expression of the NF-kappaB family members, p65 (Rel A) and p50 (NF-kappaB1), markedly reduced bortezomib-induced apoptosis. However, when we used selective genetic and chemical inhibitors of NF-kappaB, we found that NF-kappaB blockade was not sufficient to induce apoptosis of RCC cells. Thus, we conclude that maximal bortezomib-induced apoptosis is dependent on its NF-kappaB inhibitory effect, but NF-kappaB-independent effects also play a critical role in the induction of apoptosis by bortezomib. This represents the first report to formally demonstrate that bortezomib-induced NF-kappaB blockade is required to achieve the maximum degree of apoptosis by this drug.