Abstract 133: Effects of iASPP on paclitaxel-mediated mitotic catastrophe and chemoresistance in ovarian cancers

Purpose: In this study, for the first time, we aimed to investigate the expression profile of iASPP in ovarian epithelial tumor in association with clinicopathological parameters. In vitro effect of iASPP on paclitaxel chemosensitivity will also be investigated. Materials and Methods: Expression and amplification status of iASPP was examined in 140 clinical samples and 16 ovarian cell lines using immunohistochemistry, immunoblotting and quantitative real-time PCR, and correlated with clinicopathological parameters. Changes in proliferation, mitotic catastrophe and apoptosis in ovarian cancer cell lines of different p53 status following paclitaxel exposure were also analyzed using TUNEL assay, MTT assay and immunofluorescence. Results: By immunohistochemistry and quantitative PCR, significantly higher protein and mRNA levels of iASPP was found in ovarian cancers when compared with borderline and benign ovarian tumour samples. Higher iASPP expression was also found in ovarian cancer cell lines than normal ovarian epithelial cell lines. Higher iASPP expression was significantly associated with carboplatin and paclitaxel chemoresistance (P=0.04), shorter overall (P=0.003) and disease-free survival (P=0.001). Multivariate analysis confirmed iASPP expression as an independent prognostic factor. Increased iASPP mRNA expression was significantly correlated with its gene amplification (P=0.018), suggesting that gene amplification contributes to overexpression of iASPP in ovarian caner. By in vitro assay, we demonstrated that iASPP overexpression in ovarian cancer cells conferred resistance to paclitaxel by reducing mitotic catastrophe in a p53-independent manner via activation of separase whilst knockdown of iASPP enhanced paclitaxel-mediated mitotic catastrophe through inactivating separase. Both securin and cyclin B1/CDK1complex were involved in regulating separase by iASPP. Conversely, overexpressed iASPP inhibited apoptosis in a p53-dependent mode. Conclusion: Our findings suggested that iASPP may be explored as a potential prognostic marker and a novel molecular target for chemotherapy of ovarian cancers, especially in patients with chemoresistant or recurrent cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 133.