Article: iASPP and chemoresistance in ovarian cancers: Effects on paclitaxel-mediated mitotic catastrophe
| Title | iASPP and chemoresistance in ovarian cancers: Effects on paclitaxel-mediated mitotic catastrophe |
|---|---|
| Authors | Jiang, L1 2 Siu, MKY2 Wong, OGW2 Tam, KF2 Lu, X5 Lam, EWF3 Ngan, HYS2 Le, XF4 Wong, ESY2 Monteiro, LJ3 Chan, HY2 Cheung, ANY2 |
| Issue Date | 2011 |
| Publisher | American Association for Cancer Research. |
| Citation | Clinical 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 |
| 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. |
| ISSN | 1078-0432 2011 Impact Factor: 7.742 2011 SCImago Journal Rankings: 1.066 |
| DOI | http://dx.doi.org/10.1158/1078-0432.CCR-11-0588 |
| References | References in Scopus |
| Grants | Akt and p21-activated kinase signaling pathways in gestational trophoblastic disease |
| dc.contributor.author | Jiang, L | ||||||
|---|---|---|---|---|---|---|---|
| dc.contributor.author | Siu, MKY | ||||||
| dc.contributor.author | Wong, OGW | ||||||
| dc.contributor.author | Tam, KF | ||||||
| dc.contributor.author | Lu, X | ||||||
| dc.contributor.author | Lam, EWF | ||||||
| dc.contributor.author | Ngan, HYS | ||||||
| dc.contributor.author | Le, XF | ||||||
| dc.contributor.author | Wong, ESY | ||||||
| dc.contributor.author | Monteiro, LJ | ||||||
| dc.contributor.author | Chan, HY | ||||||
| dc.contributor.author | Cheung, ANY | ||||||
| dc.date.accessioned | 2012-05-29T06:14:25Z | ||||||
| dc.date.available | 2012-05-29T06:14:25Z | ||||||
| dc.date.issued | 2011 | ||||||
| dc.description.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. | ||||||
| dc.description.grant | Akt and p21-activated kinase signaling pathways in gestational trophoblastic disease | ||||||
| dc.description.grantcode | 82405 | ||||||
| dc.description.nature | Link_to_subscribed_fulltext | ||||||
| dc.identifier.citation | Clinical 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.doi | http://dx.doi.org/10.1158/1078-0432.CCR-11-0588 | ||||||
| dc.identifier.epage | 6933 | ||||||
| dc.identifier.hkuros | 202232 | ||||||
| dc.identifier.isi | WOS:000296624000036
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.issn | 1078-0432 2011 Impact Factor: 7.742 2011 SCImago Journal Rankings: 1.066 | ||||||
| dc.identifier.issue | 21 | ||||||
| dc.identifier.pmid | 21926165 | ||||||
| dc.identifier.scopus | eid_2-s2.0-80455129998 | ||||||
| dc.identifier.spage | 6924 | ||||||
| dc.identifier.uri | http://hdl.handle.net/10722/148656 | ||||||
| dc.identifier.volume | 17 | ||||||
| dc.language | eng | ||||||
| dc.publisher | American Association for Cancer Research. | ||||||
| dc.publisher.place | United States | ||||||
| dc.relation.ispartof | Clinical Cancer Research | ||||||
| dc.relation.references | References in Scopus | ||||||
| dc.subject.mesh | Antineoplastic Agents, Phytogenic - pharmacology | ||||||
| dc.subject.mesh | Mitosis - drug effects | ||||||
| dc.subject.mesh | Ovarian Neoplasms - drug therapy - metabolism - pathology | ||||||
| dc.subject.mesh | Paclitaxel - pharmacology | ||||||
| dc.subject.mesh | Repressor Proteins - biosynthesis - genetics | ||||||
| dc.title | iASPP and chemoresistance in ovarian cancers: Effects on paclitaxel-mediated mitotic catastrophe | ||||||
| dc.type | Article |
Author Affiliations
- Sichuang University
- The University of Hong Kong
- Imperial College London
- University of Texas M. D. Anderson Cancer Center
- University of Oxford