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Article: iASPP and chemoresistance in ovarian cancers: Effects on paclitaxel-mediated mitotic catastrophe

TitleiASPP and chemoresistance in ovarian cancers: Effects on paclitaxel-mediated mitotic catastrophe
Authors
Issue Date2011
PublisherAmerican Association for Cancer Research.
Citation
Clinical Cancer Research, 2011, v. 17 n. 21, p. 6924-6933 How to Cite?
Abstract
Purpose: iASPP is a specific regulator of p53-mediated apoptosis. Herein, we provided the first report on the expression profile of iASPP in ovarian epithelial tumor and its effect on paclitaxel chemosensitivity. Experimental Design: Expression and amplification status of iASPP was examined in 203 clinical samples and 17 cell lines using immunohistochemistry, quantitative real-time PCR, and immunoblotting, and correlated with clinicopathologic parameters. Changes in proliferation, mitotic catastrophe, apoptosis, and underlying mechanism in ovarian cancer cells of different p53 status following paclitaxel exposure were also analyzed. Results: The protein and mRNA expression of iASPP was found to be significantly increased in ovarian cancer samples and cell lines. High iASPP expression was significantly associated with clear cell carcinoma subtype (P = 0.003), carboplatin and paclitaxel chemoresistance (P = 0.04), shorter overall (P = 0.003), and disease-free (P = 0.001) survival. Multivariate analysis confirmed iASPP expression as an independent prognostic factor. Increased iASPP mRNA expression was significantly correlated with gene amplification (P = 0.023). iASPP overexpression in ovarian cancer cells conferred resistance to paclitaxel by reducing mitotic catastrophe in a p53-independent manner via activation of separase, whereas knockdown of iASPP enhanced paclitaxel-mediated mitotic catastrophe through inactivating separase. Both securin and cyclin B1/CDK1 complex were involved in regulating separase by iASPP. Conversely, overexpressed iASPP inhibited apoptosis in a p53-dependent mode. Conclusions: Our data show an association of iASPP overexpression with gene amplification in ovarian cancer and suggest a role of iASPP in poor patient outcome and chemoresistance, through blocking mitotic catastrophe. iASPP should be explored further as a potential prognostic marker and target for chemotherapy. ©2011 AACR.
Persistent Identifierhttp://hdl.handle.net/10722/148656
ISSN
2013 Impact Factor: 8.193
2013 SCImago Journal Rankings: 5.150
ISI Accession Number ID
Funding AgencyGrant Number
Council of the Hong Kong Special Administrative RegionHKU 7503/06M
AntiCancer Society
Funding Information:

This study was supported by funding from the Research Grants Council of the Hong Kong Special Administrative Region (HKU 7503/06M) and AntiCancer Society Fund.

References
Grants

 

Author Affiliations
  1. The University of Hong Kong
  2. Imperial College London
  3. University of Texas M. D. Anderson Cancer Center
  4. University of Oxford
  5. Sichuan University
DC FieldValueLanguage
dc.contributor.authorJiang, Len_HK
dc.contributor.authorSiu, MKYen_HK
dc.contributor.authorWong, OGWen_HK
dc.contributor.authorTam, KFen_HK
dc.contributor.authorLu, Xen_HK
dc.contributor.authorLam, EWFen_HK
dc.contributor.authorNgan, HYSen_HK
dc.contributor.authorLe, XFen_HK
dc.contributor.authorWong, ESYen_HK
dc.contributor.authorMonteiro, LJen_HK
dc.contributor.authorChan, HYen_HK
dc.contributor.authorCheung, ANYen_HK
dc.date.accessioned2012-05-29T06:14:25Z-
dc.date.available2012-05-29T06:14:25Z-
dc.date.issued2011en_HK
dc.identifier.citationClinical Cancer Research, 2011, v. 17 n. 21, p. 6924-6933en_HK
dc.identifier.issn1078-0432en_HK
dc.identifier.urihttp://hdl.handle.net/10722/148656-
dc.description.abstractPurpose: iASPP is a specific regulator of p53-mediated apoptosis. Herein, we provided the first report on the expression profile of iASPP in ovarian epithelial tumor and its effect on paclitaxel chemosensitivity. Experimental Design: Expression and amplification status of iASPP was examined in 203 clinical samples and 17 cell lines using immunohistochemistry, quantitative real-time PCR, and immunoblotting, and correlated with clinicopathologic parameters. Changes in proliferation, mitotic catastrophe, apoptosis, and underlying mechanism in ovarian cancer cells of different p53 status following paclitaxel exposure were also analyzed. Results: The protein and mRNA expression of iASPP was found to be significantly increased in ovarian cancer samples and cell lines. High iASPP expression was significantly associated with clear cell carcinoma subtype (P = 0.003), carboplatin and paclitaxel chemoresistance (P = 0.04), shorter overall (P = 0.003), and disease-free (P = 0.001) survival. Multivariate analysis confirmed iASPP expression as an independent prognostic factor. Increased iASPP mRNA expression was significantly correlated with gene amplification (P = 0.023). iASPP overexpression in ovarian cancer cells conferred resistance to paclitaxel by reducing mitotic catastrophe in a p53-independent manner via activation of separase, whereas knockdown of iASPP enhanced paclitaxel-mediated mitotic catastrophe through inactivating separase. Both securin and cyclin B1/CDK1 complex were involved in regulating separase by iASPP. Conversely, overexpressed iASPP inhibited apoptosis in a p53-dependent mode. Conclusions: Our data show an association of iASPP overexpression with gene amplification in ovarian cancer and suggest a role of iASPP in poor patient outcome and chemoresistance, through blocking mitotic catastrophe. iASPP should be explored further as a potential prognostic marker and target for chemotherapy. ©2011 AACR.en_HK
dc.languageengen_US
dc.publisherAmerican Association for Cancer Research.-
dc.relation.ispartofClinical Cancer Researchen_HK
dc.subject.meshAntineoplastic Agents, Phytogenic - pharmacologyen_US
dc.subject.meshMitosis - drug effectsen_US
dc.subject.meshOvarian Neoplasms - drug therapy - metabolism - pathologyen_US
dc.subject.meshPaclitaxel - pharmacologyen_US
dc.subject.meshRepressor Proteins - biosynthesis - geneticsen_US
dc.titleiASPP and chemoresistance in ovarian cancers: Effects on paclitaxel-mediated mitotic catastropheen_HK
dc.typeArticleen_HK
dc.identifier.emailSiu, MKY: mkysiu@hkucc.hku.hken_HK
dc.identifier.emailNgan, HYS: hysngan@hkucc.hku.hken_HK
dc.identifier.emailCheung, ANY: anycheun@hkucc.hku.hken_HK
dc.identifier.authoritySiu, MKY=rp00275en_HK
dc.identifier.authorityNgan, HYS=rp00346en_HK
dc.identifier.authorityCheung, ANY=rp00542en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1158/1078-0432.CCR-11-0588en_HK
dc.identifier.pmid21926165en_HK
dc.identifier.scopuseid_2-s2.0-80455129998en_HK
dc.identifier.hkuros202232-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-80455129998&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume17en_HK
dc.identifier.issue21en_HK
dc.identifier.spage6924en_HK
dc.identifier.epage6933en_HK
dc.identifier.eissn1557-3265-
dc.identifier.isiWOS:000296624000036-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectAkt and p21-activated kinase signaling pathways in gestational trophoblastic disease-
dc.identifier.scopusauthoridJiang, L=36801738800en_HK
dc.identifier.scopusauthoridSiu, MKY=24924018400en_HK
dc.identifier.scopusauthoridWong, OGW=7004813981en_HK
dc.identifier.scopusauthoridTam, KF=54417988200en_HK
dc.identifier.scopusauthoridLu, X=26643632100en_HK
dc.identifier.scopusauthoridLam, EWF=7102889877en_HK
dc.identifier.scopusauthoridNgan, HYS=34571944100en_HK
dc.identifier.scopusauthoridLe, XF=16637748300en_HK
dc.identifier.scopusauthoridWong, ESY=23101622300en_HK
dc.identifier.scopusauthoridMonteiro, LJ=35330377400en_HK
dc.identifier.scopusauthoridChan, HY=26024081600en_HK
dc.identifier.scopusauthoridCheung, ANY=54927484100en_HK

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