title: Cell death by bortezomib-induced mitotic catastrophe in natural killer lymphoma cells.
abstract: The proteasome inhibitor bortezomib (PS-341/Velcade) is used for the treatment of relapsed and refractory multiple myeloma and mantle-cell lymphoma. We recently reported its therapeutic potential against natural killer (NK)-cell neoplasms. Here, we investigated the molecular mechanisms of bortezomib-induced cell death in NK lymphoma cells. NK lymphoma cell lines (SNK-6 and NK-YS) and primary cultures of NK lymphomas treated with bortezomib were examined for alterations in cell viability, apoptosis, cellular senescence, and cell cycle status. Bortezomib primarily induced mitochondrial apoptosis in NK-YS cells and in primary lymphoma cells at the same concentration as reported in myeloma cells. Unexpectedly, SNK-6 cells required a significantly higher median inhibitory concentration of bortezomib (23 nmol/L) than NK-YS and primary lymphoma cells (6-13 nmol/L). Apoptosis was limited in SNK-6 cells due to the extensively delayed turnover of Bcl-2 family members. These cells were killed by bortezomib, albeit at higher pharmacologic concentrations, via mitotic catastrophe-a mitotic cell death associated with M-phase arrest, cyclin B1 accumulation, and increased CDC2/CDK1 activity. Our results suggest that, in addition to cell death by apoptosis at lower bortezomib concentrations, NK lymphoma cells resistant to bortezomib-induced apoptosis can be killed via mitotic catastrophe, an alternative cell death mechanism, at higher pharmacologic concentrations of bortezomib. Hence, activating mitotic catastrophe by bortezomib may provide a novel therapeutic approach for treating apoptosis-resistant NK-cell malignancies and other cancers.
authors.affiliation: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, People's Republic of China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Shen
authors.forename: Wing-Yan
authors.initials: WY
authors.lastname: Au
authors.forename: Kai-Yau
authors.initials: KY
authors.lastname: Wong
authors.forename: Norio
authors.initials: N
authors.lastname: Shimizu
authors.forename: Junjiro
authors.initials: J
authors.lastname: Tsuchiyama
authors.forename: Yok-Lam
authors.initials: YL
authors.lastname: Kwong
authors.forename: Raymond H
authors.initials: RH
authors.lastname: Liang
authors.forename: Gopesh
authors.initials: G
authors.lastname: Srivastava
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002453:Cell Cycle; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D053938:DNA Fragmentation; D005434:Flow Cytometry; D006801:Humans; D020128:Inhibitory Concentration 50; D007694:Killer Cells, Natural / Q000166:cytology / Q000378:metabolism*; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D008938:Mitosis; D008954:Models, Biological; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D011719:Pyrazines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib