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Article: Role of MEK/ERK pathway in the MAD2-mediated cisplatin sensitivity in testicular germ cell tumour cells

TitleRole of MEK/ERK pathway in the MAD2-mediated cisplatin sensitivity in testicular germ cell tumour cells
Authors
Issue Date2006
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/bjc
Citation
British Journal Of Cancer, 2006, v. 95 n. 4, p. 475-484 How to Cite?
AbstractTesticular germ cell tumour (TGCT) is the most common malignancy in young males. Although most TGCTs are sensitive to cisplatin-based chemotherapy, significant numbers of TGCT patients still relapse and die each year because of the development of resistance to cisplatin. Previously, we first reported that a key regulator of the mitotic checkpoint, mitotic arrest deficient-2 (MAD2), was a mediator of cisplatin sensitivity in human cancer cells. In this study, we investigated whether MAD2 played a role in cellular sensitivity to cisplatin in TGCT cells and the underlying molecular mechanisms responsible. Using 10 TGCT cell lines, we found that increased MAD2 expression was correlated with cellular sensitivity to cisplatin, which was associated with activation of the MEK pathway. Treatment of cells expressing high levels of MAD2 with an MEK inhibitor, U0126, led to cellular protection against cisplatin-induced apoptosis. Inactivation of MAD2 by transfecting a dominant-negative construct in TGCT cells with high levels of MAD2 resulted in the suppression of MEK pathway and resistance to cisplatin-induced cell death. These results support previous suggestion on the involvement of mitotic checkpoint in DNA damage response in human cancer cells and demonstrate a possible molecular mechanism responsible for the MAD2-mediated sensitivity to cisplatin in TGCT cells. Our results also suggest that downregulation of MAD2 may be an indicator for identification of TGCT cancer cells that are potentially resistant to cisplatin-based therapy. © 2006 Cancer Research.
Persistent Identifierhttp://hdl.handle.net/10722/67567
ISSN
2015 Impact Factor: 5.569
2015 SCImago Journal Rankings: 2.939
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorFung, MKLen_HK
dc.contributor.authorCheung, HWen_HK
dc.contributor.authorLing, MTen_HK
dc.contributor.authorCheung, ALMen_HK
dc.contributor.authorWong, YCen_HK
dc.contributor.authorWang, Xen_HK
dc.date.accessioned2010-09-06T05:56:17Z-
dc.date.available2010-09-06T05:56:17Z-
dc.date.issued2006en_HK
dc.identifier.citationBritish Journal Of Cancer, 2006, v. 95 n. 4, p. 475-484en_HK
dc.identifier.issn0007-0920en_HK
dc.identifier.urihttp://hdl.handle.net/10722/67567-
dc.description.abstractTesticular germ cell tumour (TGCT) is the most common malignancy in young males. Although most TGCTs are sensitive to cisplatin-based chemotherapy, significant numbers of TGCT patients still relapse and die each year because of the development of resistance to cisplatin. Previously, we first reported that a key regulator of the mitotic checkpoint, mitotic arrest deficient-2 (MAD2), was a mediator of cisplatin sensitivity in human cancer cells. In this study, we investigated whether MAD2 played a role in cellular sensitivity to cisplatin in TGCT cells and the underlying molecular mechanisms responsible. Using 10 TGCT cell lines, we found that increased MAD2 expression was correlated with cellular sensitivity to cisplatin, which was associated with activation of the MEK pathway. Treatment of cells expressing high levels of MAD2 with an MEK inhibitor, U0126, led to cellular protection against cisplatin-induced apoptosis. Inactivation of MAD2 by transfecting a dominant-negative construct in TGCT cells with high levels of MAD2 resulted in the suppression of MEK pathway and resistance to cisplatin-induced cell death. These results support previous suggestion on the involvement of mitotic checkpoint in DNA damage response in human cancer cells and demonstrate a possible molecular mechanism responsible for the MAD2-mediated sensitivity to cisplatin in TGCT cells. Our results also suggest that downregulation of MAD2 may be an indicator for identification of TGCT cancer cells that are potentially resistant to cisplatin-based therapy. © 2006 Cancer Research.en_HK
dc.languageengen_HK
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/bjcen_HK
dc.relation.ispartofBritish Journal of Canceren_HK
dc.subject.meshButadienes - pharmacologyen_HK
dc.subject.meshCalcium-Binding Proteins - pharmacologyen_HK
dc.subject.meshCell Cycle Proteins - pharmacologyen_HK
dc.subject.meshCell Line, Tumoren_HK
dc.subject.meshCisplatin - therapeutic useen_HK
dc.subject.meshDown-Regulationen_HK
dc.subject.meshDrug Resistance, Neoplasmen_HK
dc.subject.meshHumansen_HK
dc.subject.meshMAP Kinase Kinase 1 - metabolismen_HK
dc.subject.meshMaleen_HK
dc.subject.meshMitogen-Activated Protein Kinase 3 - metabolismen_HK
dc.subject.meshModels, Biologicalen_HK
dc.subject.meshNeoplasms, Germ Cell and Embryonalen_HK
dc.subject.meshNitriles - pharmacologyen_HK
dc.subject.meshRepressor Proteins - pharmacologyen_HK
dc.subject.meshSignal Transductionen_HK
dc.subject.meshTesticular Neoplasms - drug therapyen_HK
dc.subject.meshTransfectionen_HK
dc.titleRole of MEK/ERK pathway in the MAD2-mediated cisplatin sensitivity in testicular germ cell tumour cellsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0007-0920&volume=95&spage=475&epage=484&date=2006&atitle=Role+of+MEK/ERK+pathway+in+the+MAD2-mediated+cisplatin+sensitivity+in+testicular+germ+cell+tumour+cellsen_HK
dc.identifier.emailLing, MT:patling@hkucc.hku.hken_HK
dc.identifier.emailCheung, ALM:lmcheung@hkucc.hku.hken_HK
dc.identifier.emailWong, YC:ycwong@hkucc.hku.hken_HK
dc.identifier.authorityLing, MT=rp00449en_HK
dc.identifier.authorityCheung, ALM=rp00332en_HK
dc.identifier.authorityWong, YC=rp00316en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1038/sj.bjc.6603284en_HK
dc.identifier.pmid16880791-
dc.identifier.scopuseid_2-s2.0-33747158763en_HK
dc.identifier.hkuros127165en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33747158763&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume95en_HK
dc.identifier.issue4en_HK
dc.identifier.spage475en_HK
dc.identifier.epage484en_HK
dc.identifier.isiWOS:000239877500009-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridFung, MKL=8718040400en_HK
dc.identifier.scopusauthoridCheung, HW=7201839381en_HK
dc.identifier.scopusauthoridLing, MT=7102229780en_HK
dc.identifier.scopusauthoridCheung, ALM=7401806497en_HK
dc.identifier.scopusauthoridWong, YC=7403041798en_HK
dc.identifier.scopusauthoridWang, X=7501854829en_HK
dc.identifier.citeulike783668-

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