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Article: c-Met overexpression contributes to the acquired apoptotic resistance of nonadherent ovarian cancer cells through a cross talk mediated by phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1/2

Titlec-Met overexpression contributes to the acquired apoptotic resistance of nonadherent ovarian cancer cells through a cross talk mediated by phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1/2
Authors
Issue Date2010
PublisherNeoplasia Press. The Journal's web site is located at http://www.neoplasia.org
Citation
Neoplasia, 2010, v. 12 n. 2, p. 128-138 How to Cite?
AbstractOvarian cancer is the most lethal gynecologic cancer mainly because of widespread peritoneal dissemination and malignant ascites. Key to this is the capacity of tumor cells to escape suspension-induced apoptosis (anoikis), which also underlies their resistance to chemotherapy. Here, we used a nonadherent cell culture model to investigate the molecular mechanisms of apoptotic resistance of ovarian cancer cells that may mimic the chemoresistance found in solid tumors. We found that ovarian cancer cells acquired a remarkable resistance to anoikis and apoptosis induced by exposure to clinically relevant doses of two front-line chemotherapeutic drugs cisplatin and paclitaxel when grown in three-dimensional than monolayer cultures. Inhibition of the hepatocyte growth factor (HGF) receptor c-Met, which is frequently overexpressed in ovarian cancer, by a specific inhibitor or small interfering RNA blocked the acquired anoikis resistance and restored chemosensitivity in three-dimensional not in two-dimensional cultures. These effects were found to be dependent on both phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) 1/2 signaling pathways. Inhibitors of PI3K/Akt abrogated ERK1/2 activation and its associated anoikis resistance in response to HGF, suggesting a signaling relay between these two pathways. Furthermore, we identified a central role of Ras as a mechanism of this cross talk. Interestingly, Ras did not lie upstream of PI3K/Akt, whereas PI3K/Akt signaling to ERK1/2 involved Ras. These findings shed new light on the apoptotic resistance mechanism of nonadherent ovarian cancer ascites cells and may have important clinical implications. Copyright © 2010 Neoplasia Press, Inc. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/148617
ISSN
2014 Impact Factor: 4.252
2015 SCImago Journal Rankings: 2.541
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Research7599/05M
Committee on Research and ConferenceHKU200807176203
HKU Outstanding Young Researcher
Funding Information:

This study was supported by grants from the Hong Kong Research Grant Council 7599/05M, Committee on Research and Conference Grant HKU200807176203, and HKU Outstanding Young Researcher Award to A.S.T.W. The authors have nothing to disclose.

References

 

DC FieldValueLanguage
dc.contributor.authorTang, MKSen_HK
dc.contributor.authorZhou, HYen_HK
dc.contributor.authorYam, JWPen_HK
dc.contributor.authorWong, ASTen_HK
dc.date.accessioned2012-05-29T06:14:08Z-
dc.date.available2012-05-29T06:14:08Z-
dc.date.issued2010en_HK
dc.identifier.citationNeoplasia, 2010, v. 12 n. 2, p. 128-138en_HK
dc.identifier.issn1522-8002en_HK
dc.identifier.urihttp://hdl.handle.net/10722/148617-
dc.description.abstractOvarian cancer is the most lethal gynecologic cancer mainly because of widespread peritoneal dissemination and malignant ascites. Key to this is the capacity of tumor cells to escape suspension-induced apoptosis (anoikis), which also underlies their resistance to chemotherapy. Here, we used a nonadherent cell culture model to investigate the molecular mechanisms of apoptotic resistance of ovarian cancer cells that may mimic the chemoresistance found in solid tumors. We found that ovarian cancer cells acquired a remarkable resistance to anoikis and apoptosis induced by exposure to clinically relevant doses of two front-line chemotherapeutic drugs cisplatin and paclitaxel when grown in three-dimensional than monolayer cultures. Inhibition of the hepatocyte growth factor (HGF) receptor c-Met, which is frequently overexpressed in ovarian cancer, by a specific inhibitor or small interfering RNA blocked the acquired anoikis resistance and restored chemosensitivity in three-dimensional not in two-dimensional cultures. These effects were found to be dependent on both phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) 1/2 signaling pathways. Inhibitors of PI3K/Akt abrogated ERK1/2 activation and its associated anoikis resistance in response to HGF, suggesting a signaling relay between these two pathways. Furthermore, we identified a central role of Ras as a mechanism of this cross talk. Interestingly, Ras did not lie upstream of PI3K/Akt, whereas PI3K/Akt signaling to ERK1/2 involved Ras. These findings shed new light on the apoptotic resistance mechanism of nonadherent ovarian cancer ascites cells and may have important clinical implications. Copyright © 2010 Neoplasia Press, Inc. All rights reserved.en_HK
dc.languageengen_US
dc.publisherNeoplasia Press. The Journal's web site is located at http://www.neoplasia.orgen_HK
dc.relation.ispartofNeoplasiaen_HK
dc.subject.meshAnoikis - Drug Effects - Physiologyen_US
dc.subject.meshAntineoplastic Agents - Pharmacologyen_US
dc.subject.meshBlotting, Westernen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshCisplatin - Pharmacologyen_US
dc.subject.meshDrug Resistance, Neoplasm - Physiologyen_US
dc.subject.meshEnzyme Activation - Drug Effects - Physiologyen_US
dc.subject.meshFemaleen_US
dc.subject.meshHepatocyte Growth Factor - Metabolismen_US
dc.subject.meshHumansen_US
dc.subject.meshIn Situ Nick-End Labelingen_US
dc.subject.meshMitogen-Activated Protein Kinase 1 - Metabolismen_US
dc.subject.meshMitogen-Activated Protein Kinase 3 - Metabolismen_US
dc.subject.meshOvarian Neoplasms - Metabolismen_US
dc.subject.meshPaclitaxel - Pharmacologyen_US
dc.subject.meshPhosphatidylinositol 3-Kinases - Metabolismen_US
dc.subject.meshProto-Oncogene Proteins C-Met - Metabolismen_US
dc.subject.meshReceptor Cross-Talk - Drug Effects - Physiologyen_US
dc.subject.meshReverse Transcriptase Polymerase Chain Reactionen_US
dc.subject.meshSignal Transduction - Drug Effects - Physiologyen_US
dc.subject.meshRas Proteins - Metabolismen_US
dc.titlec-Met overexpression contributes to the acquired apoptotic resistance of nonadherent ovarian cancer cells through a cross talk mediated by phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1/2en_HK
dc.typeArticleen_HK
dc.identifier.emailYam, JWP: jywp@hkucc.hku.hken_HK
dc.identifier.emailWong, AST: awong1@hkucc.hku.hken_HK
dc.identifier.authorityYam, JWP=rp00468en_HK
dc.identifier.authorityWong, AST=rp00805en_HK
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1593/neo.91438en_HK
dc.identifier.pmid20126471-
dc.identifier.pmcidPMC2814351-
dc.identifier.scopuseid_2-s2.0-76749107447en_HK
dc.identifier.hkuros174117-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-76749107447&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume12en_HK
dc.identifier.issue2en_HK
dc.identifier.spage128en_HK
dc.identifier.epage138en_HK
dc.identifier.isiWOS:000274409000003-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridTang, MKS=16742726200en_HK
dc.identifier.scopusauthoridZhou, HY=7404742310en_HK
dc.identifier.scopusauthoridYam, JWP=6603711123en_HK
dc.identifier.scopusauthoridWong, AST=23987963300en_HK

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