MP20-05 LATROPHILINS AS DOWNSTREAM EFFECTORS OF THE ANDROGEN RECEPTOR INDUCE PROSTATE CANCER PROGRESSION

Abstract

You have accessJournal of UrologyCME1 Apr 2023MP20-05 LATROPHILINS AS DOWNSTREAM EFFECTORS OF THE ANDROGEN RECEPTOR INDUCE PROSTATE CANCER PROGRESSION Yuki Teramoto, Takuro Goto, Masato Yasui, and Hiroshi Miyamoto Yuki TeramotoYuki Teramoto More articles by this author , Takuro GotoTakuro Goto More articles by this author , Masato YasuiMasato Yasui More articles by this author , and Hiroshi MiyamotoHiroshi Miyamoto More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003245.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Latrophilins (LPHNs), including LPHN1, LPHN2, and LPHN3, are a group of the G-protein-coupled receptor where a spider venom latrotoxin (LTX) is known to bind. Alterations in their encoded genes (e.g. ADGRL1, ADGRL2, ADGRL3) have been linked to susceptibility to attention deficit hyperactivity disorder (ADHD). Interestingly, ADHD is diagnosed approximately 3 times more often in boys than in girls, and prenatal exposure to excess androgens has been suggested to increase its risk. However, LPHNs remain largely uncharacterized in neoplastic diseases. The present study aimed to determine the functional role of LPHNs in the progression of prostate cancer. METHODS: In human prostate cancer lines, we assessed the effects of androgen receptor (AR) ligands and LPHN ligands (e.g. LTX, FLRT3) or silencing of each LPHN via shRNA virus infection on the expression of LPHNs and the cell growth/expression of related proteins, respectively. In 150 radical prostatectomy cases, we immunohistochemically stained for LPHN1/LPHN2/LPHN3. RESULTS: In AR-positive LNCaP/C4-2/CWR22Rv1 cells, dihydrotestosterone treatment considerably increased the expression levels of LPHN1, LPHN2, and LPHN3, which was at least partially restored by AR inhibitors, bicalutamide and enzalutamide. Chromatin immunoprecipitation assay further revealed the binding of endogenous ARs, including ARv7, to the promoter region of each LPHN in prostate cancer cells. Treatment with LTX or FLRT3 resulted in induction in the cell viability and migration of AR-positive lines, as well as the expression of prostate-specific antigen, and reduction in apoptosis. LTX/FLRT3 also enhanced the expression of phosphorylated forms of JAK2 and STAT3, as well as Bcl-2. Meanwhile, knockdown of LPHN1, LPHN2, or LPHN3 showed opposite effects on all of those described above for LTX/FLRT3 treatment. In addition, similar stimulation by LTX/FLRT3 treatment or inhibition by knockdown of each LPHN was seen in AR-negative PC-3 and DU145 cells. In immunohistochemistry, high LPHN1 (H-score >200; HR=3.706, p=0.006)/LPHN2 (>100; HR=6.023, p=0.002)/LPHN3 (>200; HR=4.265, p=0.004) was associated with a significantly higher risk of biochemical recurrence after prostatectomy even in a multivariate setting. CONCLUSIONS: These findings indicate that LPHNs, as downstream effectors of the ARs, promote the growth of prostate cancer. LPHNs could thus be independent prognosticators in prostate cancer patients undergoing radical prostatectomy, as well as therapeutic targets for both androgen-sensitive and castration-resistant tumors. Source of Funding: NA © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e276 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yuki Teramoto More articles by this author Takuro Goto More articles by this author Masato Yasui More articles by this author Hiroshi Miyamoto More articles by this author Expand All Advertisement PDF downloadLoading ...