Targeting transcription factor NFκB: Comparative analysis of proteasome and IKK inhibitors

Nuclear factorκB (NFκB) plays a critical role in cancer development and progression. Thus, the NFκB signaling pathway provides important targets for cancer chemoprevention and anticancer chemotherapy. The central steps in NFκB activation are phosphorylation and proteasome-dependent degradation of its inhibitory proteins termed IκBs. Consequently, the major pharmacological approaches to target NFκB include (1) repression of IκB kinases (IKKs) and (2) blocking the degradation of IκBs by proteasome inhibitors. We quantitatively compared the efficacy of various proteasome inhibitors (MG132, lactacystin and epoxomicin) and IKK inhibitors (BAY 11-7082 and PS1145) to block NFκB activity induced by TNFα or TPA and to sensitize LNCaP prostate carcinoma cells to apoptosis. Our studies revealed significant differences between these two classes of NFκB inhibitors. We found that proteasome inhibitors epoxomicin and MG132 attenuated NFκB induction much more effectively than the IKK inhibitors. Furthermore, in contrast to IKK inhibitors, all studied proteasome inhibitors specifically blocked TPA-induced generation de novo of NFκB p50 homodimers-(p50/p50). These results suggest that the proteasome plays a dominant role in TPA-induced formation of functional p50 homodimers, while IKK activity is less important for this process. Interestingly, profound attenuation of p50/p50 DNA-binding does not reduce the high potency of proteasome inhibitors to suppress NFκB-dependent transcription. Finally, proteasome inhibitors were much more effective in sensitizing LNCaP cells to TNFα-induced apoptosis compared to IKK inhibitors at the concentrations when both types of agents similarly attenuated NFκB activity. We conclude that this remarkable pro-apoptotic potential of proteasome inhibitors is partially mediated through NFκB-independent mechanism.