106 INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN-2 (IGFBP-2) ALTERS PTEN ACTIVITY AND REDUCES THE EFFICACY OF DOCETAXEL IN THE TREATMENT OF PROSTATE CANCER (PCA)

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research I1 Apr 2010106 INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN-2 (IGFBP-2) ALTERS PTEN ACTIVITY AND REDUCES THE EFFICACY OF DOCETAXEL IN THE TREATMENT OF PROSTATE CANCER (PCA) Christopher Uzoh, Jeff Holly, Raj Persad, Amit Bahl, and Claire Perks Christopher UzohChristopher Uzoh More articles by this author , Jeff HollyJeff Holly More articles by this author , Raj PersadRaj Persad More articles by this author , Amit BahlAmit Bahl More articles by this author , and Claire PerksClaire Perks More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.155AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES PCa is 5th most diagnosed cancer, worldwide. Aggressive disease, androgen-independence and treatment failure are predominant reasons for high mortality. We aim to identify new molecular targets that can be exploited to slow progression. Inactivation of tumor suppressor genes, changes in androgen regulation and activation of the insulin-like growth factor axis are common events in PCa pathogenesis and progression. Tumor suppressor gene PTEN is most frequently mutated in metastatic PCa and it dictates progression. IGFBP-2 can modulate IGF actions but also has intrinsic, IGF-independent actions, promoting growth of PCa cells. Its levels increase 2-3-fold in serum of PCa patients and correlate with serum PSA and Gleason score. It plays a key role in promoting androgen-independent and metastatic phenotype and is a biomarker of PTEN status. However, its mechanism of action and relationship to PTEN remain unknown. METHODS DU145 and PC3 PCa cell lines were treated with either IGFBP-2 (0-1000ng/ml)(GroPep, Australia) or IGFBP-2 siRNA (50nM)(Qiagen, UK) +/- PTEN inhibitor (0.1μM) (Axxora, UK) assessing growth and PTEN changes. We compared the sensitivity of the cells to Docetaxel-induced cell death (30nM) in the presence or absence of IGFBP-2 using siRNA. Tritiated thymidine incorporation (TTI) measured growth and Trypan blue dye exclusion assay assessed cell death. Western immunoblotting assessed changes in PTEN status and apoptosis was confirmed by PARP cleavage. Statistical analysis was done using ANOVA. RESULTS IGFBP-2 caused dose-dependent increase in TTI and cell counting in DU145 and PC3 cells, maximal at 250ng/ml (P<0.01). Conversely, in DU145 cells, the absence of IGFBP-2 significantly (P<0.001) inhibited cell growth. Addition of IGFBP-2 had no effect on total PTEN but significantly increased its phosphorylation; associated with inactivation and promoting growth. The effect of IGFBP-2 siRNA was negated in the presence of PTEN inhibitor indicating that the effects of IGFBP-2 on growth were mediated by PTEN. We showed further that the sensitivity of the cells to Docetaxel-induced cell death was significantly increased in absence of IGFBP-2, suggesting that IGFBP-2 is a survival factor. CONCLUSIONS IGFBP-2 is a potent mitogen and survival factor for human PCa cells; effects involving PTEN inactivation. PCa cells are more sensitive to apoptosis-inducing agents when IGFBP-2 has been silenced. These data may have important implications for the management of androgen independent prostate cancer. Bristol, United Kingdom© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e43-e44 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christopher Uzoh More articles by this author Jeff Holly More articles by this author Raj Persad More articles by this author Amit Bahl More articles by this author Claire Perks More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...