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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 1
 
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
2012 Impact Factor: 5.599
2012 SCImago Journal Rankings: 2.387
 
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
2012 Impact Factor: 5.599
2012 SCImago Journal Rankings: 2.387
 
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