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

¹ Institut National de la Sante et de la Recherche Medicale, UMR601; ² Université de Nantes, Nantes Atlantique Universités, UFR Médecine et Techniques Médicales; ³ Equipe 5 labélisée Ligue Nationale contre le Cancer 2005; ⁴ Institut National de la Sante et de la Recherche Medicale ERI 7; ⁵ Centre Hospitalier Universitaire, Service d'Hématologie Clinique, Nantes, France

Requests for reprints: Martine Amiot, Institut National de la Sante et de la Recherche Medicale, U601, Département de recherche en Cancérologie, 9 quai Moncousu, Nantes, F-44000 France. Phone: 33-2-40-08-47-66; Fax: 33-2-40-08-47-78; E-mail: mamiot{at}nantes.inserm.fr.

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]

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