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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.

Original publication

DOI

10.1158/1078-0432.CCR-11-0588

Type

Journal article

Journal

Clin Cancer Res

Publication Date

01/11/2011

Volume

17

Pages

6924 - 6933

Keywords

Adult, Aged, Antineoplastic Agents, Phytogenic, Cell Cycle Proteins, Cell Line, Tumor, Cyclin B1, Drug Resistance, Neoplasm, Endopeptidases, Female, Gene Amplification, Humans, Immunohistochemistry, Intracellular Signaling Peptides and Proteins, Middle Aged, Mitosis, Neoplasm Proteins, Ovarian Neoplasms, Paclitaxel, RNA, Messenger, Real-Time Polymerase Chain Reaction, Repressor Proteins, Securin, Separase, Survival Rate, Tumor Suppressor Protein p53, Up-Regulation, Young Adult