title: Natural killer cells suppress enzalutamide resistance and cell invasion in the castration resistant prostate cancer via targeting the androgen receptor splicing variant 7 (ARv7).
abstract: Despite the success of androgen-deprivation therapy (ADT) with the newly developed anti-androgen enzalutamide (Enz, also known as MDV3100) to suppress castration resistant prostate cancer (CRPC) in extending patient survival by an extra 4.8 months, eventually patients die with the development of Enz resistance that may involve the induction of the androgen receptor (AR) splicing variant ARv7. Here we identify an unrecognized role of Natural Killer (NK) cells in the prostate tumor microenvironment that can be better recruited to the CRPC cells to suppress ARv7 expression resulting in suppressing the Enz resistant CRPC cell growth and invasion. Mechanism dissection revealed that CRPC cells, compared to normal prostate epithelial cells, could recruit more NK cells that might then lead to alterations of the microRNA-34 and microRNA-449 to suppress both ARv7 expression and ARv7-induced EZH2 expression to suppress CRPC cell invasion. Together, these results identify a new potential therapy using recruited NK cells to better suppress the Enz resistance and cell invasion in CRPC at the later enzalutamide resistant stage.
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Shin-Jen
authors.initials: SJ
authors.lastname: Lin
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Fu-Ju
authors.initials: FJ
authors.lastname: Chou
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA; Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Chang-Yi
authors.initials: CY
authors.lastname: Lin
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Yeh
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, 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.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D017398:Alternative Splicing; D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002634:Chemotaxis, Leukocyte; D018920:Coculture Techniques; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009570:Nitriles; D010641:Phenotype; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms; D011944:Receptors, Androgen / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D001549:Benzamides; C522425:MIRN34 microRNA, human; C544530:MIRN449 microRNA, human; D035683:MicroRNAs; D009570:Nitriles; D020033:Protein Isoforms; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein
keywords: ARv7; Enzalutamide; Natural Killer cells