title: Mitotic catastrophe and cell cycle arrest are alternative cell death pathways executed by bortezomib in rituximab resistant B-cell lymphoma cells.
abstract: The ubiqutin-proteasome system (UPS) plays a role in rituximab-chemotherapy resistance and bortezomib (BTZ) possesses caspase-dependent (i.e. Bak stabilization) and a less characterized caspase-independent mechanism-of-action(s). Here, we define BTZ-induced caspase-independent cell death pathways. A panel of rituximab-sensitive (RSCL), rituximab-resistant cell lines (RRCL) and primary tumor cells derived from lymphoma patients (N = 13) were exposed to BTZ. Changes in cell viability, cell-cycle, senescence, and mitotic index were quantified. In resting conditions, RRCL exhibits a low-proliferation rate, accumulation of cells in S-phase and senescence. Exposure of RRCL to BTZ reduces cell senescence, induced G2-M phase cell-cycle arrest, and is associated with mitotic catastrophe. BTZ stabilized p21, CDC2, and cyclin B in RRCL and in primary tumor cells. Transient p21 knockdown alleviates BTZ-induced senescence inhibition, G2-M cell cycle blockade, and mitotic catastrophe. Our data suggest that BTZ can induce apoptosis or mitotic catastrophe and that p21 has a pivotal role in BTZ activity against RRCL.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Gu
authors.affiliation: Department of Internal Medicine, Mayo Clinic, Rochester, MN, Celgene Corporation, Summit, NJ, USA.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Kaufman
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Cory
authors.initials: C
authors.lastname: Mavis
authors.forename: Myron S
authors.initials: MS
authors.lastname: Czuczman
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Hernandez-Ilizaliturri
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000069286:Bortezomib / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000473:pathology*; D008938:Mitosis / Q000187:drug effects*; D000069283:Rituximab / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D000069283:Rituximab; D000069286:Bortezomib
keywords: B-cell lymphoma; bortezomib; rituximab