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Article: Cell death by bortezomib-induced mitotic catastrophe in natural killer lymphoma cells
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TitleCell death by bortezomib-induced mitotic catastrophe in natural killer lymphoma cells
 
AuthorsShen, L1
Au, WY1
Wong, KY1
Shimizu, N2
Tsuchiyama, J3
Kwong, YL1
Liang, RH1
Srivastava, G1
 
Issue Date2008
 
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://mct.aacrjournals.org/
 
CitationMolecular Cancer Therapeutics, 2008, v. 7 n. 12, p. 3807-3815 [How to Cite?]
DOI: http://dx.doi.org/10.1158/1535-7163.MCT-08-0641
 
AbstractThe 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. Copyright © 2008 American Association for Cancer Research.
 
ISSN1535-7163
2013 Impact Factor: 6.107
2013 SCImago Journal Rankings: 3.117
 
DOIhttp://dx.doi.org/10.1158/1535-7163.MCT-08-0641
 
ISI Accession Number IDWOS:000261848500016
Funding AgencyGrant Number
Research Grants Council of Hong Kong Special Administrative Region, People's Republic of ChinaHKU 7627/06M
Funding Information:

Research Grants Council of Hong Kong Special Administrative Region, People's Republic of China grant HKU 7627/06M (G. Srivastava and R.H. Liang).

 
ReferencesReferences in Scopus
 
GrantsTherapeutic potential and mechanisms of antitumor activity of proteasome inhibitor bortezomib in extranodal NK/T-cell lymphoma, nasal type
 
DC FieldValue
dc.contributor.authorShen, L
 
dc.contributor.authorAu, WY
 
dc.contributor.authorWong, KY
 
dc.contributor.authorShimizu, N
 
dc.contributor.authorTsuchiyama, J
 
dc.contributor.authorKwong, YL
 
dc.contributor.authorLiang, RH
 
dc.contributor.authorSrivastava, G
 
dc.date.accessioned2010-05-31T03:46:13Z
 
dc.date.available2010-05-31T03:46:13Z
 
dc.date.issued2008
 
dc.description.abstractThe 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. Copyright © 2008 American Association for Cancer Research.
 
dc.description.naturelink_to_subscribed_fulltext
 
dc.identifier.citationMolecular Cancer Therapeutics, 2008, v. 7 n. 12, p. 3807-3815 [How to Cite?]
DOI: http://dx.doi.org/10.1158/1535-7163.MCT-08-0641
 
dc.identifier.doihttp://dx.doi.org/10.1158/1535-7163.MCT-08-0641
 
dc.identifier.eissn1538-8514
 
dc.identifier.epage3815
 
dc.identifier.hkuros159811
 
dc.identifier.isiWOS:000261848500016
Funding AgencyGrant Number
Research Grants Council of Hong Kong Special Administrative Region, People's Republic of ChinaHKU 7627/06M
Funding Information:

Research Grants Council of Hong Kong Special Administrative Region, People's Republic of China grant HKU 7627/06M (G. Srivastava and R.H. Liang).

 
dc.identifier.issn1535-7163
2013 Impact Factor: 6.107
2013 SCImago Journal Rankings: 3.117
 
dc.identifier.issue12
 
dc.identifier.openurl
 
dc.identifier.pmid19074855
 
dc.identifier.scopuseid_2-s2.0-57749106962
 
dc.identifier.spage3807
 
dc.identifier.urihttp://hdl.handle.net/10722/59252
 
dc.identifier.volume7
 
dc.languageeng
 
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://mct.aacrjournals.org/
 
dc.publisher.placeUnited States
 
dc.relation.ispartofMolecular Cancer Therapeutics
 
dc.relation.projectTherapeutic potential and mechanisms of antitumor activity of proteasome inhibitor bortezomib in extranodal NK/T-cell lymphoma, nasal type
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshAntineoplastic Agents - pharmacology
 
dc.subject.meshApoptosis
 
dc.subject.meshBoronic Acids - pharmacology
 
dc.subject.meshCell Aging
 
dc.subject.meshCell Cycle
 
dc.subject.meshCell Line, Tumor
 
dc.subject.meshDNA Fragmentation
 
dc.subject.meshFlow Cytometry
 
dc.subject.meshHumans
 
dc.subject.meshInhibitory Concentration 50
 
dc.subject.meshKiller Cells, Natural - cytology - metabolism
 
dc.subject.meshLymphoma - drug therapy - pathology
 
dc.subject.meshMitosis
 
dc.subject.meshModels, Biological
 
dc.subject.meshMultiple Myeloma - drug therapy - pathology
 
dc.subject.meshPyrazines - pharmacology
 
dc.titleCell death by bortezomib-induced mitotic catastrophe in natural killer lymphoma cells
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong
  2. Tokyo Medical and Dental University
  3. Kawasaki Medical College