Dysregulation of unfolded protein response partially underlies proapoptotic activity of bortezomib in multiple myeloma cells.

The 26S proteasome inhibitor, bortezomib, has shown remarkable therapeutic efficacy in multiple myeloma (MM), however, the mechanism by which this compound acts remains unknown. Here, we have demonstrated that bortezomib targets the prototypical expression of unfolded protein response (UPR) genes BiP, CHOP and XBP-1 at the mRNA and protein levels, resulting in induction of proapoptotic UPR outputs and suppression of cytoprotective UPR components, leading to caspase-dependent apoptosis in human MM H929 and 8226/S cell lines. Moreover, knockdown of XPB-1s, via lentivirus-mediated RNA interference approach, sensitises MM cells to apoptosis induction by bortezomib. Together, these data strongly suggest that dysregulated or disruptive UPR may, at least partly, underlie the antimyeloma activity of bortezomib.