Endoplasmic-reticulum Stress Pathway-associated Mechanisms of Action of Proteasome Inhibitors in Multiple Myeloma

Bortezomib (BTZ), a proteasome inhibitor, was initially reported as an inhibitor of the NF-κB pathway, which plays a critical role in the pathogenesis of multiple myeloma (MM). The NF-κB activity of MM cells is mediated via two distinct pathways, canonical and non-canonical, which show opposing activity after BTZ treatment in MM cells. Recent studies of proteasome inhibition in MM cells reveal that the accumulation of unfolded proteins in the endoplasmic reticulum (ER), referred to as ER stress, triggered the activity of several pro-apoptotic factors and sources of cell stress, such as the accumulation of reactive oxygen species (ROS), which is considered to be the main mechanism of action of BTZ-induced apoptosis. Several factors associated with ER stress and unfolded protein response (UPR) have been identified with the sensitivity of BTZ treatment. Low levels of XBP1, ATF3, and ATF4, which regulate UPR and ER stress-induced apoptosis, have been observed in poor responders to BTZ treatment, and three other genes, KLF9, Nampt, and CDK5, are associated with response to BTZ-containing therapy. These findings contribute to a better understanding of the mechanisms underlying BTZ-induced apoptosis in MM cells; however, further study is needed to develop potential predictive biomarkers of efficacy of BTZ-containing therapy.