Noxa Up-regulation and Mcl-1 Cleavage Are Associated to Apoptosis Induction by Bortezomib in Multiple Myeloma

Abstract

Targeting the ubiquitin-proteasome pathway has emerged as a potent anticancer strategy. Bortezomib, a specific proteasome inhibitor, has been approved for the treatment of relapsed or refractory multiple myeloma. Multiple myeloma cell survival is highly dependent on Mcl-1 antiapoptotic molecules. In a recent study, proteasome inhibitors induced Mcl-1 accumulation that slowed down their proapoptotic effects. Consequently, we investigated the role of Bcl-2 family members in bortezomib-induced apoptosis. We found that bortezomib induced apoptosis in five of seven human myeloma cell lines (HMCL). Bortezomib-induced apoptosis was associated with Mcl-1 cleavage regardless of Mcl-1L accumulation. Furthermore, RNA interference mediated Mcl-1 decrease and sensitized RPMI-8226 HMCL to bortezomib, highlighting the contribution of Mcl-1 in bortezomib-induced apoptosis. Interestingly, an important induction of Noxa was found in all sensitive HMCL both at protein and mRNA level. Concomitant to Mcl-1 cleavage and Noxa induction, we also found caspase-3, caspase-8, and caspase-9 activation. Under bortezomib treatment, Mcl-1L/Noxa complexes were highly increased, Mcl-1/Bak complexes were disrupted, and there was an accumulation of free Noxa. Finally, we observed a dissociation of Mcl-1/Bim complexes that may be due to a displacement of Bim induced by Noxa. Thus, in myeloma cells, the mechanistic basis for bortezomib sensitivity can be explained mainly by the model in which the sensitizer Noxa can displace Bim, a BH3-only activator, from Mcl-1, thus leading to Bax/Bak activation. [Cancer Res 2007;67(11):5418-24]

Differential effects of anti-apoptotic Bcl-2 family members Mcl-1, Bcl-2, and Bcl-xL on Celecoxib-induced apoptosis

“…Interestingly, RNAi-mediated silencing of Noxa clearly inhibited Celecoxib-induced apoptosis indicating a major role of Noxa during Celecoxib-induced apoptosis. A similar involvement of the Mcl-1/Noxa axis in apoptosis induction has been shown for further chemotherapeutic agents including camptothecin, the cyclin-dependent kinase inhibitor Seliciclib, the proteasome inhibitor bortezomib, histone deacetylsae inhibitors, arsenic trioxide, and glucose withdrawal [28][29][30][31][32][33].…”

Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737

“…This is contrary to the observation that Noxa mediates Mcl-1 degradation in mouse embryo fibroblasts and HeLa cells based in part on the unique properties of the COOH-terminal region of the Noxa BH3 domain (28,29). One might attribute the differences to cell typespecific variation, but an inverse correlation between Noxa and Mcl-1 expression has been seen in a variety of cell types (34,35) and expression of Noxa in the H209 cell line clearly leads to a proportionate decline in Mcl-1 expression (Fig. 4).…”

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

“…The high protein synthesis rates of MM cells (compared with low protein synthesis rates of normal cells) may render them uniquely sensitive to ER stress-mediated apoptosis (Meister et al, 2007;Nawrocki et al, 2008). Earlier studies have demonstrated that bortezomib-induced NOXA expression and ER stress-mediated apoptosis in MM cells is a result of a large accrual of ubiquitinated proteins (Fernandez et al, 2005;Qin et al, 2005;Perez-Galan et al, 2006;Gomez-Bougie et al, 2007;Nawrocki et al, 2008;Wang et al, 2009). Similarly to proteasomal inhibition, unchecked viral replication in malignant cells leads to an accumulation of viral proteins.…”