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Article: CD133 + HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway

TitleCD133 + HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway
Authors
KeywordsCancer stem cells
CD133
Chemoresistance
HCC
Survival
Issue Date2008
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
Citation
Oncogene, 2008, v. 27 n. 12, p. 1749-1758 How to Cite?
AbstractThe recent discovery of cancer stem cells (CSCs) has played a pivotal role in changing our view of carcinogenesis and chemotherapy. Based on this concept, CSCs are responsible for the formation and growth of neoplastic tissue and are naturally resistant to chemotherapy, explaining why traditional chemotherapies can initially shrink a tumor but fails to eradicate it in full, allowing eventual recurrence. Recently, we identified a CSC population in hepatocellular carcinoma (HCC) characterized by their CD133 phenotype. However, the molecular mechanism by which it escapes conventional therapies remains unknown. Here, we examined the sensitivity of these cells to chemotherapeutic agents (doxorubicin and fluorouracil) and the possible mechanistic pathway by which resistance may be regulated. Purified CD133 + HCC cells isolated from human HCC cell line and xenograft mouse models survived chemotherapy in increased proportions relative to most tumor cells which lack the CD133 phenotype; the underlying mechanism of which required the preferential expression of survival proteins involved in the Akt/PKB and Bcl-2 pathway. Treatment of CD133 + HCC cells with an AKT1 inhibitor, specific to the Akt/PKB pathway, significantly reduced the expression of the survival proteins that was normally expressed endogenously. In addition, treatment of unsorted HCC cells with both anticancer drugs in vitro significantly enriched the CD133 + subpopulation. In conclusion, our results show that CD133 + HCC cells contribute to chemoresistance through preferential activation of Akt/PKB and Bcl-2 cell survival response. Targeting of this specific survival signaling pathway in CD133 + HCC CSCs may provide a novel therapeutic model for the disease. © 2008 Nature Publishing Group All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/148548
ISSN
2015 Impact Factor: 7.932
2015 SCImago Journal Rankings: 4.047
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorMa, Sen_HK
dc.contributor.authorLee, TKen_HK
dc.contributor.authorZheng, BJen_HK
dc.contributor.authorChan, KWen_HK
dc.contributor.authorGuan, XYen_HK
dc.date.accessioned2012-05-29T06:13:39Z-
dc.date.available2012-05-29T06:13:39Z-
dc.date.issued2008en_HK
dc.identifier.citationOncogene, 2008, v. 27 n. 12, p. 1749-1758en_HK
dc.identifier.issn0950-9232en_HK
dc.identifier.urihttp://hdl.handle.net/10722/148548-
dc.description.abstractThe recent discovery of cancer stem cells (CSCs) has played a pivotal role in changing our view of carcinogenesis and chemotherapy. Based on this concept, CSCs are responsible for the formation and growth of neoplastic tissue and are naturally resistant to chemotherapy, explaining why traditional chemotherapies can initially shrink a tumor but fails to eradicate it in full, allowing eventual recurrence. Recently, we identified a CSC population in hepatocellular carcinoma (HCC) characterized by their CD133 phenotype. However, the molecular mechanism by which it escapes conventional therapies remains unknown. Here, we examined the sensitivity of these cells to chemotherapeutic agents (doxorubicin and fluorouracil) and the possible mechanistic pathway by which resistance may be regulated. Purified CD133 + HCC cells isolated from human HCC cell line and xenograft mouse models survived chemotherapy in increased proportions relative to most tumor cells which lack the CD133 phenotype; the underlying mechanism of which required the preferential expression of survival proteins involved in the Akt/PKB and Bcl-2 pathway. Treatment of CD133 + HCC cells with an AKT1 inhibitor, specific to the Akt/PKB pathway, significantly reduced the expression of the survival proteins that was normally expressed endogenously. In addition, treatment of unsorted HCC cells with both anticancer drugs in vitro significantly enriched the CD133 + subpopulation. In conclusion, our results show that CD133 + HCC cells contribute to chemoresistance through preferential activation of Akt/PKB and Bcl-2 cell survival response. Targeting of this specific survival signaling pathway in CD133 + HCC CSCs may provide a novel therapeutic model for the disease. © 2008 Nature Publishing Group All rights reserved.en_HK
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/oncen_HK
dc.relation.ispartofOncogeneen_HK
dc.subjectCancer stem cellsen_HK
dc.subjectCD133en_HK
dc.subjectChemoresistanceen_HK
dc.subjectHCCen_HK
dc.subjectSurvivalen_HK
dc.subject.meshAnimalsen_US
dc.subject.meshAntigens, Cd - Biosynthesis - Physiologyen_US
dc.subject.meshCarcinoma, Hepatocellular - Metabolismen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshCell Survival - Drug Effects - Physiologyen_US
dc.subject.meshDrug Resistance, Neoplasm - Physiologyen_US
dc.subject.meshGlycoproteins - Biosynthesis - Physiologyen_US
dc.subject.meshHumansen_US
dc.subject.meshLiver Neoplasms - Drug Therapy - Enzymologyen_US
dc.subject.meshMap Kinase Signaling System - Drug Effects - Physiologyen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Nudeen_US
dc.subject.meshNeoplastic Stem Cells - Drug Effects - Metabolismen_US
dc.subject.meshPeptides - Physiologyen_US
dc.subject.meshProto-Oncogene Proteins C-Akt - Biosynthesis - Physiologyen_US
dc.subject.meshSignal Transduction - Drug Effects - Physiologyen_US
dc.subject.meshTransplantation, Heterologousen_US
dc.subject.meshTumor Cells, Cultureden_US
dc.titleCD133 + HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathwayen_HK
dc.typeArticleen_HK
dc.identifier.emailMa, S:sma@pathology.hku.hken_HK
dc.identifier.emailLee, TK:tkwlee@hkucc.hku.hken_HK
dc.identifier.emailZheng, BJ:bzheng@hkucc.hku.hken_HK
dc.identifier.emailChan, KW:hrmtckw@hku.hken_HK
dc.identifier.emailGuan, XY:xyguan@hkucc.hku.hken_HK
dc.identifier.authorityMa, S=rp00506en_HK
dc.identifier.authorityLee, TK=rp00447en_HK
dc.identifier.authorityZheng, BJ=rp00353en_HK
dc.identifier.authorityChan, KW=rp00330en_HK
dc.identifier.authorityGuan, XY=rp00454en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1038/sj.onc.1210811en_HK
dc.identifier.pmid17891174-
dc.identifier.scopuseid_2-s2.0-40749150740en_HK
dc.identifier.hkuros142915-
dc.identifier.hkuros144435-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-40749150740&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume27en_HK
dc.identifier.issue12en_HK
dc.identifier.spage1749en_HK
dc.identifier.epage1758en_HK
dc.identifier.eissn1476-5594-
dc.identifier.isiWOS:000253962100010-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.f10001096034-
dc.identifier.scopusauthoridMa, S=16444895800en_HK
dc.identifier.scopusauthoridLee, TK=7501439435en_HK
dc.identifier.scopusauthoridZheng, BJ=7201780588en_HK
dc.identifier.scopusauthoridChan, KW=16444133100en_HK
dc.identifier.scopusauthoridGuan, XY=7201463221en_HK
dc.identifier.citeulike1795271-

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