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Article: Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells

TitleLoss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells
Authors
Issue Date2008
PublisherOxford University Press. The Journal's web site is located at http://carcin.oxfordjournals.org/
Citation
Carcinogenesis, 2008, v. 29 n. 9, p. 1742-1750 How to Cite?
AbstractThe RAS-RAF-MEK-extracellular signal-regulated kinase (ERK) pathway plays a pivotal role in various cellular responses, including cellular growth, differentiation, survival and motility. Constitutive activation of the ERK pathway has been linked to the development and progression of human cancers. Here, we reported that mitogen-activated protein kinase phosphatase (MKP)-3, a negative regulator of ERK1/2, lost its expression particularly in the protein level, was significantly correlated with high ERK1/2 activity in primary human ovarian cancer cells using quantitative reverse transcription-polymerase chain reaction and western blot analyses. Intriguingly, the loss of MKP3 protein was associated with ubiquitination/proteosome degradation mediated by high intracellular reactive oxygen species (ROS) accumulation such as hydrogen peroxide in ovarian cancer cells. Functionally, short hairpin RNA knock down of endogenous MKP3 resulted in increased ERK1/2 activity, cell proliferation rate, anchorage-independent growth ability and resistance to cisplatin in ovarian cancer cells. Conversely, enforced expression of MKP3 in MKP3-deficient ovarian cancer cells significantly reduced ERK1/2 activity and inhibited cell proliferation, anchorage-independent growth ability and tumor development in nude mice. Furthermore, the enforced expression of MKP3 succeeded to sensitize ovarian cancer cells to cisplatin-induced apoptosis in vitro and in vivo. These results suggest a molecular mechanism by which the accumulation of ROS during ovarian cancer progression may cause the degradation of MKP3, which in turn leads to aberrant ERK1/2 activation and contributes to tumorigenicity and chemoresistance of human ovarian cancer cells. © The Author 2008. Published by Oxford University Press. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/58182
ISSN
2015 Impact Factor: 4.874
2015 SCImago Journal Rankings: 2.439
ISI Accession Number ID
Funding AgencyGrant Number
University of Hong Kong10207308
Wong Check She Charitable Foundation
Ministry of Education, Culture, Sports, Science and Technology of Japan
Funding Information:

CRCG of the University of Hong Kong (10207308); Wong Check She Charitable Foundation; Program for Promoting the Establishment of Strategic Research Centers, Special Coordination Funds for Promoting Science and Technology, Ministry of Education, Culture, Sports, Science and Technology of Japan to T. F.

References

 

DC FieldValueLanguage
dc.contributor.authorChan, DWen_HK
dc.contributor.authorLiu, VWSen_HK
dc.contributor.authorTsao, GSWen_HK
dc.contributor.authorYao, KMen_HK
dc.contributor.authorFurukawa, Ten_HK
dc.contributor.authorChan, KKLen_HK
dc.contributor.authorNgan, HYSen_HK
dc.date.accessioned2010-05-31T03:25:21Z-
dc.date.available2010-05-31T03:25:21Z-
dc.date.issued2008en_HK
dc.identifier.citationCarcinogenesis, 2008, v. 29 n. 9, p. 1742-1750en_HK
dc.identifier.issn0143-3334en_HK
dc.identifier.urihttp://hdl.handle.net/10722/58182-
dc.description.abstractThe RAS-RAF-MEK-extracellular signal-regulated kinase (ERK) pathway plays a pivotal role in various cellular responses, including cellular growth, differentiation, survival and motility. Constitutive activation of the ERK pathway has been linked to the development and progression of human cancers. Here, we reported that mitogen-activated protein kinase phosphatase (MKP)-3, a negative regulator of ERK1/2, lost its expression particularly in the protein level, was significantly correlated with high ERK1/2 activity in primary human ovarian cancer cells using quantitative reverse transcription-polymerase chain reaction and western blot analyses. Intriguingly, the loss of MKP3 protein was associated with ubiquitination/proteosome degradation mediated by high intracellular reactive oxygen species (ROS) accumulation such as hydrogen peroxide in ovarian cancer cells. Functionally, short hairpin RNA knock down of endogenous MKP3 resulted in increased ERK1/2 activity, cell proliferation rate, anchorage-independent growth ability and resistance to cisplatin in ovarian cancer cells. Conversely, enforced expression of MKP3 in MKP3-deficient ovarian cancer cells significantly reduced ERK1/2 activity and inhibited cell proliferation, anchorage-independent growth ability and tumor development in nude mice. Furthermore, the enforced expression of MKP3 succeeded to sensitize ovarian cancer cells to cisplatin-induced apoptosis in vitro and in vivo. These results suggest a molecular mechanism by which the accumulation of ROS during ovarian cancer progression may cause the degradation of MKP3, which in turn leads to aberrant ERK1/2 activation and contributes to tumorigenicity and chemoresistance of human ovarian cancer cells. © The Author 2008. Published by Oxford University Press. All rights reserved.en_HK
dc.languageengen_HK
dc.publisherOxford University Press. The Journal's web site is located at http://carcin.oxfordjournals.org/en_HK
dc.relation.ispartofCarcinogenesisen_HK
dc.rightsCarcinogenesis. Copyright © Lippincott Williams & Wilkins.en_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshApoptosis - drug effects - physiologyen_HK
dc.subject.meshBlotting, Westernen_HK
dc.subject.meshCell Adhesion - physiologyen_HK
dc.subject.meshCell Proliferation - drug effectsen_HK
dc.subject.meshCisplatin - pharmacologyen_HK
dc.subject.meshDisease Progressionen_HK
dc.subject.meshDrug Resistance, Neoplasmen_HK
dc.subject.meshDual Specificity Phosphatase 6 - antagonists & inhibitors - genetics - metabolismen_HK
dc.subject.meshFemaleen_HK
dc.subject.meshHumansen_HK
dc.subject.meshHydrogen Peroxide - metabolismen_HK
dc.subject.meshMiceen_HK
dc.subject.meshMitogen-Activated Protein Kinase 1 - antagonists & inhibitors - metabolismen_HK
dc.subject.meshMitogen-Activated Protein Kinase 3 - antagonists & inhibitors - metabolismen_HK
dc.subject.meshOvarian Neoplasms - drug therapy - genetics - pathologyen_HK
dc.subject.meshOxidative Stress - physiologyen_HK
dc.subject.meshPhosphorylationen_HK
dc.subject.meshPromoter Regions, Geneticen_HK
dc.subject.meshRNA, Messenger - antagonists & inhibitors - genetics - metabolismen_HK
dc.subject.meshReverse Transcriptase Polymerase Chain Reactionen_HK
dc.subject.meshSignal Transduction - drug effectsen_HK
dc.subject.meshTumor Cells, Cultureden_HK
dc.subject.meshUbiquitin - metabolismen_HK
dc.titleLoss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cellsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0147-4006&volume=29&issue=9&spage=1742&epage=1750&date=2008&atitle=Loss+of+MKP3+mediated+by+oxidative+stress+enhances+tumorigenicity+and+chemoresistance+of+ovarian+cancer+cellsen_HK
dc.identifier.emailChan, DW: dwchan@hku.hken_HK
dc.identifier.emailLiu, VWS: vwsliu@hkusua.hku.hken_HK
dc.identifier.emailTsao, GSW: gswtsao@hku.hken_HK
dc.identifier.emailYao, KM: kmyao@hku.hken_HK
dc.identifier.emailChan, KKL: kklchan@hkucc.hku.hken_HK
dc.identifier.emailNgan, HYS: hysngan@hkucc.hku.hken_HK
dc.identifier.authorityChan, DW=rp00543en_HK
dc.identifier.authorityLiu, VWS=rp00341en_HK
dc.identifier.authorityTsao, GSW=rp00399en_HK
dc.identifier.authorityYao, KM=rp00344en_HK
dc.identifier.authorityChan, KKL=rp00499en_HK
dc.identifier.authorityNgan, HYS=rp00346en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1093/carcin/bgn167en_HK
dc.identifier.pmid18632752-
dc.identifier.scopuseid_2-s2.0-51849123638en_HK
dc.identifier.hkuros145619en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-51849123638&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume29en_HK
dc.identifier.issue9en_HK
dc.identifier.spage1742en_HK
dc.identifier.epage1750en_HK
dc.identifier.eissn1460-2180-
dc.identifier.isiWOS:000258961200010-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridChan, DW=26533900600en_HK
dc.identifier.scopusauthoridLiu, VWS=7006405113en_HK
dc.identifier.scopusauthoridTsao, GSW=7102813116en_HK
dc.identifier.scopusauthoridYao, KM=7403234578en_HK
dc.identifier.scopusauthoridFurukawa, T=35392252000en_HK
dc.identifier.scopusauthoridChan, KKL=8655666700en_HK
dc.identifier.scopusauthoridNgan, HYS=34571944100en_HK

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