title: Anti-androgen enzalutamide enhances prostate cancer neuroendocrine (NE) differentiation via altering the infiltrated mast cells → androgen receptor (AR) → miRNA32 signals.
abstract: The recently developed anti-androgen enzalutamide also known as (MDV3100) has the advantage to prolong by 4.8 months the survival of castration resistant prostate cancer (CRPC) patients. However, the mechanisms behind the potential side effects involving the induction of the prostate cancer (PCa) neuroendocrine (NE) differentiation remain unclear. Here we found PCa cells could recruit more mast cells than normal prostate epithelial cells, and enzalutamide (or casodex) treatment could further increase such recruitment that resulted in promoting the PCa NE differentiation. Mechanism dissection found infiltrated mast cells could function through positive feedback to enhance PCa to recruit more mast cells via modulation of the androgen receptor (AR) → cytokines IL8 signals, and interruption by AR-siRNA or neutralizing anti-IL8 antibody could partially reverse the recruitment of mast cells. Importantly, targeting the PCa androgens/AR signals with AR-siRNA or enzalutamide (or casodex) also increased PCa NE differentiation via modulation of the miRNA32 expression, and adding miRNA32 inhibitor reversed the AR-siRNA- or enzalutamide-enhanced NE differentiation. Together, these results not only identified a new signal via infiltrated mast cells → PCa AR → miRNA32 to increase PCa NE differentiation, it also pointed out the potential unwanted side effects of enzalutamide (or casodex) to increase PCa NE differentiation. Targeting these newly identified signals, including AR, IL8, or miRNA32, may help us to better suppress PCa NE differentiation that is induced during ADT with anti-androgen enzalutamide (or casodex) treatment.
authors: Sex Hormone Research Center, Department of Urology, the First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China; George Whipple Lab for Cancer Research, Departments of Pathology and Urology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors: Qiang
authors: Q
authors: Dang
authors: Sex Hormone Research Center, Department of Urology, the First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China; George Whipple Lab for Cancer Research, Departments of Pathology and Urology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA. Electronic address: lilydr@163.com.
authors: Lei
authors: L
authors: Li
authors: Sex Hormone Research Center, Department of Urology, the First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China; George Whipple Lab for Cancer Research, Departments of Pathology and Urology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors: Hongjun
authors: H
authors: Xie
authors: Sex Hormone Research Center, Department of Urology, the First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors: Dalin
authors: D
authors: He
authors: Sex Hormone Research Center, Department of Urology, the First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors: Jiaqi
authors: J
authors: Chen
authors: Sex Hormone Research Center, Department of Urology, the First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China; George Whipple Lab for Cancer Research, Departments of Pathology and Urology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors: Wenbing
authors: W
authors: Song
authors: Sex Hormone Research Center, Department of Urology, the First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors: Luke S
authors: LS
authors: Chang
authors: George Whipple Lab for Cancer Research, Departments of Pathology and Urology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors: Hong-Chiang
authors: HC
authors: Chang
authors: George Whipple Lab for Cancer Research, Departments of Pathology and Urology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors: Shuyuan
authors: S
authors: Yeh
authors: George Whipple Lab for Cancer Research, Departments of Pathology and Urology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA; Sex Hormone Research Center, China Medical University/Hospital, Taichung 404, Taiwan. Electronic address: chang@urmc.rochester.edu.
authors: Chawnshang
authors: C
authors: Chang
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D055099:Neuroendocrine Cells / Q000473:pathology*; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000726:Androgen Antagonists; D001549:Benzamides; C568529:MIRN32 microRNA, human; D035683:MicroRNAs; D009570:Nitriles; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide
keywords: IL8; Mast cells; NE differentiation; Prostate cancer; miRNA32