MP55-01 CYTOPLASMIC FOXO1 NEGATIVELY REGULATES ERK TO OVERCOME TAXOL RESISTANCE IN PROSTATE CANCER (2015)

You have accessJournal of UrologyProstate Cancer: Basic Research III1 Apr 2015MP55-01 CYTOPLASMIC FOXO1 NEGATIVELY REGULATES ERK TO OVERCOME TAXOL RESISTANCE IN PROSTATE CANCER Chunwu Pan, Jian An, Yunqian Pan, Liguo Wang, Jun Zhang, Jun Qi, and Haojie Huang Chunwu PanChunwu Pan More articles by this author , Jian AnJian An More articles by this author , Yunqian PanYunqian Pan More articles by this author , Liguo WangLiguo Wang More articles by this author , Jun ZhangJun Zhang More articles by this author , Jun QiJun Qi More articles by this author , and Haojie HuangHaojie Huang More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2044AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES O-class forkhead factor 1 (FoxO1) acts as a tumor suppressor in the nucleus through its transcriptional function. FOXO1 can be phosphorylated by activated protein kinase B (AKT) and exported to cytoplasm, thereby losing its tumor suppressor function. The PI3K/AKT signaling is frequently hyperactivated in human cancers, and inhibitors of PI3K/AKT are currently tested in various preclinical and clinical settings. Intriguingly, inhibition of PI3K/AKT invariably triggers activation of extracellular signal-regulated kinase (ERK) signaling, which is an important mechanism of chemoresistance. Here we identify a transcription-independent tumor suppressor function of FOXO1 in the cytoplasm, finding of which has significant applications in overcoming taxol chemoresistance through inhibiting ERK signaling in prostate cancer. METHODS We employed unbiased tandem affinity purification (TAP) and mass spectrometry to identify interacting proteins of FOXO1. We used GST-Pulldown and co-immuniprecipitation (co-IP) to define the interaction domains in both IQGAP1 and FOXO1, Western-blot to detect the protein expression level, immunocytochemistry (ICC) to detect FOXO1 cellular localization, immunohistochemistry (IHC) to analysize FOXO1 and phosphor-ERK level in human prostate cancer using tissue microarray (TMA), and MTS assay to determine cells proliferation. RESULTS We identified the scaffold protein IQGAP1 as a binding partner of FOXO1 (Fig A). We demonstrated that serine-319 phosphorylation on FOXO1 is important for FOXO1 binding to IQGAP1 (Fig B). Cytoplasmic FOXO1 inhibits IQGAP1-augmented phosphorylation of ERK1/2 by blocking IQGAP1 interaction with RAF, MEK and ERK proteins (Fig C-E). We also found that there is an inverse correlation between FOXO1 and phosphorylated ERK1/2 in human prostate cancer tissues (Fig F, G). We further demonstrated that low expression of FOXO1 and increased expression of ERK1/2 phosphorylation significantly associates with prostate cancer progression (Fig H). Finaly, we demonstrated that cytoplasmic FOXO1 inhibits PI3K/AKT inhibitor or taxol-induced ERK activation and thereby overcoming taxol-resistance in prostate cancer (Fig I-L). CONCLUSIONS Cytoplasmic FOXO1 overcomes taxol resistance in prostate cancer by negatively regulating ERK activation. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e672-e673 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Chunwu Pan More articles by this author Jian An More articles by this author Yunqian Pan More articles by this author Liguo Wang More articles by this author Jun Zhang More articles by this author Jun Qi More articles by this author Haojie Huang More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...