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Article: iASPP and chemoresistance in ovarian cancers: Effects on paclitaxel-mediated mitotic catastrophe
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TitleiASPP and chemoresistance in ovarian cancers: Effects on paclitaxel-mediated mitotic catastrophe
 
AuthorsJiang, L1 5
Siu, MKY1
Wong, OGW1
Tam, KF1
Lu, X4
Lam, EWF2
Ngan, HYS1
Le, XF3
Wong, ESY1
Monteiro, LJ2
Chan, HY1
Cheung, ANY1
 
Issue Date2011
 
PublisherAmerican Association for Cancer Research.
 
CitationClinical Cancer Research, 2011, v. 17 n. 21, p. 6924-6933 [How to Cite?]
DOI: http://dx.doi.org/10.1158/1078-0432.CCR-11-0588
 
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.
 
ISSN1078-0432
2013 Impact Factor: 8.193
2013 SCImago Journal Rankings: 5.150
 
DOIhttp://dx.doi.org/10.1158/1078-0432.CCR-11-0588
 
ISI Accession Number IDWOS:000296624000036
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.

 
ReferencesReferences in Scopus
 
GrantsAkt and p21-activated kinase signaling pathways in gestational trophoblastic disease
 
DC FieldValue
dc.contributor.authorJiang, L
 
dc.contributor.authorSiu, MKY
 
dc.contributor.authorWong, OGW
 
dc.contributor.authorTam, KF
 
dc.contributor.authorLu, X
 
dc.contributor.authorLam, EWF
 
dc.contributor.authorNgan, HYS
 
dc.contributor.authorLe, XF
 
dc.contributor.authorWong, ESY
 
dc.contributor.authorMonteiro, LJ
 
dc.contributor.authorChan, HY
 
dc.contributor.authorCheung, ANY
 
dc.date.accessioned2012-05-29T06:14:25Z
 
dc.date.available2012-05-29T06:14:25Z
 
dc.date.issued2011
 
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.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationClinical Cancer Research, 2011, v. 17 n. 21, p. 6924-6933 [How to Cite?]
DOI: http://dx.doi.org/10.1158/1078-0432.CCR-11-0588
 
dc.identifier.doihttp://dx.doi.org/10.1158/1078-0432.CCR-11-0588
 
dc.identifier.eissn1557-3265
 
dc.identifier.epage6933
 
dc.identifier.hkuros202232
 
dc.identifier.isiWOS:000296624000036
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.

 
dc.identifier.issn1078-0432
2013 Impact Factor: 8.193
2013 SCImago Journal Rankings: 5.150
 
dc.identifier.issue21
 
dc.identifier.pmid21926165
 
dc.identifier.scopuseid_2-s2.0-80455129998
 
dc.identifier.spage6924
 
dc.identifier.urihttp://hdl.handle.net/10722/148656
 
dc.identifier.volume17
 
dc.languageeng
 
dc.publisherAmerican Association for Cancer Research.
 
dc.publisher.placeUnited States
 
dc.relation.ispartofClinical Cancer Research
 
dc.relation.projectAkt and p21-activated kinase signaling pathways in gestational trophoblastic disease
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshAntineoplastic Agents, Phytogenic - pharmacology
 
dc.subject.meshMitosis - drug effects
 
dc.subject.meshOvarian Neoplasms - drug therapy - metabolism - pathology
 
dc.subject.meshPaclitaxel - pharmacology
 
dc.subject.meshRepressor Proteins - biosynthesis - genetics
 
dc.titleiASPP and chemoresistance in ovarian cancers: Effects on paclitaxel-mediated mitotic catastrophe
 
dc.typeArticle
 
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<contributor.author>Lu, X</contributor.author>
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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