Prostate carcinoma cell death resulting from inhibition of proteasome activity is independent of functional Bcl-2 and p53

The ATP/ubiquitin-dependent 26S proteasome is a central regulator of cell c ycle progression and stress responses. While investigating the application of peptide aldehyde proteasome inhibitors to block signal-induced I kappa B alpha degradation in human LNCaP prostate carcinoma cells, we observed tha t persistent inhibition of proteasomal activity signals a potent cell death program. Biochemically, this program included substantial upregulation of PAR-4 (prostate apoptosis response-4), a putative pro-apoptotic effector pr otein and stabilization of c-jun protein, a potent pro-death effector in ce rtain cells. We also observed modest downregulation of bcl-X-L, a pro-survi val effector protein. However, in contrast to some recent reports stable, h igh level, expression of functional bcl-2 protein in prostate carcinoma cel ls failed to signal protection against cell death induction by proteasome i nhibitors. Also in disagreement to a recent report, no evidence was found f or activation of the JNK stress kinase pathway, A role for p53, a protein r egulated by the proteasome pathway, was ruled out, since comparable cell de ath induction by proteasome inhibitors occurred in PC-3 cells that db not e xpress functional p53 protein. These data signify that the ubiquitin/protea some pathway represents a potential therapeutic target for prostate cancers irrespective of bcl-2 expression or p53 mutations.