MP37-07 UP REGULATION OF AMINOACID TRANSPORTER LAT1 DURING ANDROGEN DEPRIVATION THERAPY CONTRIBUTES TO ACQUISITION OF CASTRATION RESISTANCE IN PROSTATE CANCER CELLS

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research I1 Apr 2015MP37-07 UP REGULATION OF AMINOACID TRANSPORTER LAT1 DURING ANDROGEN DEPRIVATION THERAPY CONTRIBUTES TO ACQUISITION OF CASTRATION RESISTANCE IN PROSTATE CANCER CELLS Min Hui Xu, Shinichi Sakamoto, Shuhei Kamda, Mayuko Kato, Akira Kurozumi, Rika Nishikawa, Yusuke Goto, Miki Fuse, Yoshikatu Kanai, Naohiko Seki, and Tomohiko Ichikawa Min Hui XuMin Hui Xu More articles by this author , Shinichi SakamotoShinichi Sakamoto More articles by this author , Shuhei KamdaShuhei Kamda More articles by this author , Mayuko KatoMayuko Kato More articles by this author , Akira KurozumiAkira Kurozumi More articles by this author , Rika NishikawaRika Nishikawa More articles by this author , Yusuke GotoYusuke Goto More articles by this author , Miki FuseMiki Fuse More articles by this author , Yoshikatu KanaiYoshikatu Kanai More articles by this author , Naohiko SekiNaohiko Seki More articles by this author , and Tomohiko IchikawaTomohiko Ichikawa More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1270AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES L-type amino acid transporter 1(LAT1) transports essential amino acids, including leucine, which trigger the downstream m-TOR pathway. In a previous analysis, we identified up-regulation of LAT1 in androgen receptor (AR)-negative cells. We hypothesized that expression of LAT1 may be regulated by AR. This study examined 1) the association between AR and LAT1 expression, and 2) contribution of LAT1 in acquisition of castration resistance. METHODS Western blotting and real-time PCR were used to study protein and mRNA expressions. SiRNA was used to knockdown target genes. A total of 155 radical prostatectomy and prostate biopsy samples was used for immunohistochemical analyses. Cox hazard proportional models and the Kaplan-Meier method were used for statistical analysis. RESULTS LAT1 expresion was low in LNCaP cells but high in C4-2 and PC-3 cells. Knockdown of LAT1 in C4-2 cells significantly suppressed cell proliferation, migration, and invasion. Knockdown of LAT1 inhibited m-TOR related phosphorylation of p-70S6K and 4EBP-1. SiRNA of AR or blocking of AR through MDV3100(10µM) significantly increased LAT1 expression (P<0.01), while treatment with DHT (10nM) reduced LAT1 expression (P<0.05). MDV3100 plus SiLAT1 synergistically suppressed prostate cancer cell proliferation compared to single inhibition of AR or LAT1 (P<0.001). On immunohistochemical analysis, LAT1 expression was significantly higher in prostate cancer (PC) than in normal gland (P<0.001). LAT1 expression correlated with pathological stage (P=0.038) and Gleason Score (P=0.04). On Kaplan-Meier analysis, the high LAT1 group showed significantly shorter time to castration-resistant PC (CRPC) than the low LAT1 group after initiation of androgen deprivation therapy (ADT) (P=0.0002). When assessing the risk of castration resistance, lymph node metastasis (HR 4.29, P=0.0.072), bone metastasis (HR 6.63, P=0.0363), and LAT1 expression (HR 10.1, P=0.0274) were independent predictors on multivariate analysis. CONCLUSIONS During ADT, blocking of AR signaling up-regulated LAT1 expression and activated the downstream m-TOR pathway, contributing to CRPC. Dual inhibition of AR and LAT1 may be therapeutically useful in CRPC patients. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e440 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Min Hui Xu More articles by this author Shinichi Sakamoto More articles by this author Shuhei Kamda More articles by this author Mayuko Kato More articles by this author Akira Kurozumi More articles by this author Rika Nishikawa More articles by this author Yusuke Goto More articles by this author Miki Fuse More articles by this author Yoshikatu Kanai More articles by this author Naohiko Seki More articles by this author Tomohiko Ichikawa More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...