Natural killer cells suppress enzalutamide resistance and cell invasion in the castration resistant prostate cancer via targeting the androgen receptor splicing variant 7 (ARv7)

• Published in: Cancer letters 2017-07, Vol.398, p.62-69
• Main Authors: Lin, Shin-Jen, Chou, Fu-Ju, Li, Lei, Lin, Chang-Yi, Yeh, Shuyuan, Chang, Chawnshang
• Format: Article
• Language: English
• Subjects: 2-Mercaptoethanol; Adhesion; Adoptive transfer; Agar; Alternative Splicing; American Type Culture Collection; Androgen Antagonists - pharmacology; Androgen receptors; Androgens; Animals; Antibiotics; Antibodies; Antigens; Antineoplastic Agents, Hormonal - pharmacology; ARv7; Assaying; Bicarbonates; Biotechnology; Bone marrow; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Chemotaxis, Leukocyte; Clumps; Coculture Techniques; Cytotoxicity; Down-Regulation; Drug Resistance, Neoplasm; Enhancer of Zeste Homolog 2 Protein - metabolism; Enzalutamide; Gene expression; Gene silencing; Glands; Hematology, Oncology and Palliative Medicine; Humans; Immune response; Immunoglobulins; Immunotherapy; Incidence; Inhibition; Inhibitors; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Lymph nodes; Lymphocytes; Lymphocytes B; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Lysis; Male; Media; Metastasis; Mice, Nude; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Natural Killer cells; Neoplasm Invasiveness; Nucleic acids; Pathogens; Peptides; Phenotype; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - pharmacology; Pore size; Porosity; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - immunology; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; Protein Isoforms; Proteins; Receptors, Androgen - drug effects; Receptors, Androgen - metabolism; Signal Transduction - drug effects; Sodium; Solidification; Splicing; Stem cells; Time Factors; Tumor cells; Tumor Microenvironment; Xenograft Model Antitumor Assays
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2017.03.035

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.