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Article: Cell death by bortezomib-induced mitotic catastrophe in natural killer lymphoma cells

TitleCell death by bortezomib-induced mitotic catastrophe in natural killer lymphoma cells
Authors
Issue Date2008
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://mct.aacrjournals.org/
Citation
Molecular Cancer Therapeutics, 2008, v. 7 n. 12, p. 3807-3815 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/59252
ISSN
2014 Impact Factor: 5.683
2013 SCImago Journal Rankings: 3.117
ISI Accession Number ID
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).

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorShen, Len_HK
dc.contributor.authorAu, WYen_HK
dc.contributor.authorWong, KYen_HK
dc.contributor.authorShimizu, Nen_HK
dc.contributor.authorTsuchiyama, Jen_HK
dc.contributor.authorKwong, YLen_HK
dc.contributor.authorLiang, RHen_HK
dc.contributor.authorSrivastava, Gen_HK
dc.date.accessioned2010-05-31T03:46:13Z-
dc.date.available2010-05-31T03:46:13Z-
dc.date.issued2008en_HK
dc.identifier.citationMolecular Cancer Therapeutics, 2008, v. 7 n. 12, p. 3807-3815en_HK
dc.identifier.issn1535-7163en_HK
dc.identifier.urihttp://hdl.handle.net/10722/59252-
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.en_HK
dc.languageengen_HK
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://mct.aacrjournals.org/en_HK
dc.relation.ispartofMolecular Cancer Therapeuticsen_HK
dc.subject.meshAntineoplastic Agents - pharmacologyen_HK
dc.subject.meshApoptosisen_HK
dc.subject.meshBoronic Acids - pharmacologyen_HK
dc.subject.meshCell Agingen_HK
dc.subject.meshCell Cycleen_HK
dc.subject.meshCell Line, Tumoren_HK
dc.subject.meshDNA Fragmentationen_HK
dc.subject.meshFlow Cytometryen_HK
dc.subject.meshHumansen_HK
dc.subject.meshInhibitory Concentration 50en_HK
dc.subject.meshKiller Cells, Natural - cytology - metabolismen_HK
dc.subject.meshLymphoma - drug therapy - pathologyen_HK
dc.subject.meshMitosisen_HK
dc.subject.meshModels, Biologicalen_HK
dc.subject.meshMultiple Myeloma - drug therapy - pathologyen_HK
dc.subject.meshPyrazines - pharmacologyen_HK
dc.titleCell death by bortezomib-induced mitotic catastrophe in natural killer lymphoma cellsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1535-7163&volume=7&issue=12&spage=3807&epage=15&date=2008&atitle=Cell+death+by+bortezomib-induced+mitotic+catastrophe+in+natural+killer+lymphoma+cellsen_HK
dc.identifier.emailKwong, YL:ylkwong@hku.hken_HK
dc.identifier.emailLiang, RH:rliang@hku.hken_HK
dc.identifier.emailSrivastava, G:gopesh@pathology.hku.hken_HK
dc.identifier.authorityKwong, YL=rp00358en_HK
dc.identifier.authorityLiang, RH=rp00345en_HK
dc.identifier.authoritySrivastava, G=rp00365en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1158/1535-7163.MCT-08-0641en_HK
dc.identifier.pmid19074855en_HK
dc.identifier.scopuseid_2-s2.0-57749106962en_HK
dc.identifier.hkuros159811en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-57749106962&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume7en_HK
dc.identifier.issue12en_HK
dc.identifier.spage3807en_HK
dc.identifier.epage3815en_HK
dc.identifier.eissn1538-8514-
dc.identifier.isiWOS:000261848500016-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectTherapeutic potential and mechanisms of antitumor activity of proteasome inhibitor bortezomib in extranodal NK/T-cell lymphoma, nasal type-
dc.identifier.scopusauthoridShen, L=7401704659en_HK
dc.identifier.scopusauthoridAu, WY=7202383089en_HK
dc.identifier.scopusauthoridWong, KY=7404758500en_HK
dc.identifier.scopusauthoridShimizu, N=7403575308en_HK
dc.identifier.scopusauthoridTsuchiyama, J=6701325733en_HK
dc.identifier.scopusauthoridKwong, YL=7102818954en_HK
dc.identifier.scopusauthoridLiang, RH=26643224900en_HK
dc.identifier.scopusauthoridSrivastava, G=7202242238en_HK

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