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

Proteasome inhibitors are known to suppress the proteasome-mediated degradation of I kappa B alpha in stimulated cells. This results in the cytoplasmic retention of NF kappa B 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 I kappa B alpha, which then translocates to the nucleus, associates with the nuclear p65 NF kappa B, thus inhibiting the constitutive NF kappa B DNA binding activity and inducing apoptosis. The proteasome inhibition-induced nuclear translocation of I kappa B alpha is dependent on de novo protein synthesis, occurs also in other cell types, and does not require I kappa B alpha phosphorylation on Ser-32. Since NF kappa B activity is constitutively increased in many human cancers as well as in inflammatory disorders, the proteasome inhibition-induced nuclear translocation of I kappa B alpha could thus provide a new therapeutic strategy aimed at the specific inhibition of NF kappa B activity by the nuclear I kappa B alpha. (C) 2008 Elsevier Inc. All rights reserved.