Proteasome inhibitors induce apoptosis of prostate cancer cells by inducing nuclear translocation of IκBα

Abstract: Proteasome inhibitors are known to suppress the proteasome-mediated degradation of IκBα in stimulated cells. This results in the cytoplasmic retention of NFκB and its reduced nuclear transcriptional activity. In this study, we show that in the metastatic prostate cancer cells, the proteasome inhibitors exhibit a novel, previously unrecognized effect: they increase the cellular levels of IκBα, which then translocates to the nucleus, associates with the nuclear p65 NFκB, thus inhibiting the constitutive NFκB DNA binding activity and inducing apoptosis. The proteasome inhibition-induced nuclear translocation of IκBα is dependent on de novo protein synthesis, occurs also in other cell types, and does not require IκBα phosphorylation on Ser-32. Since NFκB activity is constitutively increased in many human cancers as well as in inflammatory disorders, the proteasome inhibition-induced nuclear translocation of IκBα could thus provide a new therapeutic strategy aimed at the specific inhibition of NFκB activity by the nuclear IκBα. [Copyright &y& Elsevier]