The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status.
Mantle-cell lymphoma (MCL) is a mature B-cell lymphoma with an aggressive course and generally poor prognosis. Conventional chemotherapy has little efficacy. Bortezomib is a novel, reversible, and highly specific proteasome inhibitor that appears as a new hope for MCL treatment. We have analyzed the in vitro sensitivity to bortezomib in 4 MCL cell lines and in primary tumor cells from 10 MCL patients. Bortezomib induced phosphatidylserine exposure, mitochondrial depolarization, ROS generation, Bax and Bak conformational changes, and caspase activation. In addition, ROS scavengers, but not pancaspase inhibitors, blocked all apoptosis hallmarks. Protein and mRNA-expression analysis, revealed marked up-regulation of the BH3-only protein Noxa, between 4 to 6 hours after bortezomib addition, independent of p53 status. However, this up-regulation was faster and higher in cells with functional p53. Noxa RNA interference markedly decreased sensitivity to bortezomib, pointing to this protein as a key mediator between proteasome inhibition and mitochondrial depolarization in MCL cells. Noxa interacts with the antiapoptotic protein Mcl-1 and promotes Bak release from Mcl-1, suggesting that up-regulation of Noxa might counteract Mcl-1 accumulation after bortezomib treatment. These findings should be useful to extend the therapeutic strategies in MCL patients and to improve their prognosis.
Pérez-Galán
Patricia
P
Hematopathology Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain.
Roué
Gaël
G
Villamor
Neus
N
Montserrat
Emili
E
Campo
Elias
E
Colomer
Dolors
D
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000502:physiology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53; D015854:Up-Regulation; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism
D000970:Antineoplastic Agents; C494772:BAK1 protein, human; D001897:Boronic Acids; D016166:Free Radical Scavengers; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; C498702:PMAIP1 protein, human; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein; D000069286:Bortezomib