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

Abstract

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-κB (NF-κB) pathway is considered a crucial effect in bortezomib-induced apoptosis, but the dependence on NF-κB inhibition for bortezomib-mediated death has not been formally demonstrated. Thus, we also studied the contribution of NF-κB inhibition as a mechanism of bortezomib-induced apoptosis in RCC cells, which display constitutive NF-κB activation. Ectopic expression of the NF-κB family members, p65 (Rel A) and p50 (NF-κB1), markedly reduced bortezomib-induced apoptosis. However, when we used selective genetic and chemical inhibitors of NF-κB, we found that NF-κB blockade was not sufficient to induce apoptosis of RCC cells. Thus, we conclude that maximal bortezomib-induced apoptosis is dependent on its NF-κB inhibitory effect, but NF-κB-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-κB blockade is required to achieve the maximum degree of apoptosis by this drug. Copyright © 2004 American Association for Cancer Research.