MP33-05 THE MAO INHIBITORS PHENELZINE AND CLORGYLINE REVERT ENZALUTAMIDE RESISTANCE IN CASTRATION RESISTANT PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I (MP33)1 Sep 2021MP33-05 THE MAO INHIBITORS PHENELZINE AND CLORGYLINE REVERT ENZALUTAMIDE RESISTANCE IN CASTRATION RESISTANT PROSTATE CANCER Keliang Wang, Ruizhe Fang, Jie Luo, Bosen You, Shuyuan Yeh, Jean V. Joseph, Edward M. Messing, and Chawnshang Chang Keliang WangKeliang Wang More articles by this author , Ruizhe FangRuizhe Fang More articles by this author , Jie LuoJie Luo More articles by this author , Bosen YouBosen You More articles by this author , Shuyuan YehShuyuan Yeh More articles by this author , Jean V. JosephJean V. Joseph More articles by this author , Edward M. MessingEdward M. Messing More articles by this author , and Chawnshang ChangChawnshang Chang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002042.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate cancer (PCa) remains one of the most prevalent male cancers in the United States, with over an estimated 26,000 cancer deaths annually. Presently, androgen deprivation therapy (ADT) with antiandrogens to suppress androgen synthesis or prevent androgens from binding to the androgen receptor (AR) are the standard treatments for metastatic PCa. Unfortunately, most ADT, including the recently developed potent antiandrogen enzalutamide (Enz), eventually fails. Results from clinical studies revealed that monoamine oxidase (MAO) might play key roles for the progression of some neuron disorders, including depression, Parkinson’s disease, or Alzheimer’s disease. The connection of MAO-A to the development of Enz resistance in CRPC, however, has not been investigated. METHODS: MTT assay was used to detect cell proliferation. Lentivirus packaging and cell transfection was used to construct MAO-A shRNA. qRT-PCR, RNAseq and Western blot were used to detect MAO-A levels. MAO-Glo assay was used to detect MAO-A activity. Luciferase reporter and Chromatin immunoprecipitation (ChIP) assays were performed to clarify how AR alters MAO-A. Nude mice xenograft model was established for in vivo study. CTC samples used for MAO-A expression analysis were excess “left-over” cDNA samples from an ongoing prospective blood-based CTC ARv7 study in men with metastatic CRPC. RESULTS: We illustrated that elevated MAO-A expression was increased in the Enz resistant cells. Consistently, after treated with Enz, elevated MAO-A level was detected in CTCs from patients. We also found phenelzine or clorgyline can reverse Enz resistance and clorgyline delays the development of Enz resistance. Enz can function via increasing ARv7 to increase MAO-A expression during the development of Enz resistance. Enz-increased ARv7 expression may lead to increase MAO-A expression by transcriptional regulation via direct binding to the ARE on the MAO-A 5′ promoter region. Also, ARv7 can increase the MAO-A protein stability. Targeting the MAO-A suppressed hypoxia signals to overcome Enz resistance. Targeting MAO-A signaling suppressed EnzR tumor growth in vivo. CONCLUSIONS: Here we report that high expression of MAO-A is associated with positive ARv7 detection in CRPC patients following Enz treatment. Targeting MAO-A with phenelzine or clorgyline, the FDA-approved drugs for antidepression, re-sensitize the Enz resistant (EnzR) cells to Enz treatment and further suppress EnzR cell growth in vitro and in vivo. Our findings suggest that Enz-increased ARv7 expression can transcriptionally enhance MAO-A expression resulting in Enz resistance via altering the hypoxia HIF-1α signals. Together, our results show that targeting the Enz/ARv7/MAO-A signaling with the antidepressants phenelzine or clorgyline can restore Enz sensitivity to suppress EnzR cell growth, which may indicate that these antidepression drugs can overcome the Enz resistance to further suppress the EnzR CRPC. Source of Funding: This work was supported by George H. Whipple Professorship and Natural Science Foundations of Heilongjiang Province of China (H2016030) © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e607-e608 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Keliang Wang More articles by this author Ruizhe Fang More articles by this author Jie Luo More articles by this author Bosen You More articles by this author Shuyuan Yeh More articles by this author Jean V. Joseph More articles by this author Edward M. Messing More articles by this author Chawnshang Chang More articles by this author Expand All Advertisement Loading ...