Dihydrotestosterone Increases Cytotoxic Activity of Macrophages on Prostate Cancer Cells via TRAIL

• Published in: Endocrinology (Philadelphia) Vol. 160; no. 9; pp. 2049 - 2060
• Main Authors: Lee, Geun Taek, Kim, Jeong Hyun, Kwon, Seok Joo, Stein, Mark N, Hong, Jeong Hee, Nagaya, Naoya, Billakanti, Sachin, Kim, Melina Minji, Kim, Wun-Jae, Kim, Isaac Yi
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.09.2019; Endocrine Society
• Subjects: Analysis; Androgen receptors; Androgen suppression therapy; Androgens; Animals; Antibodies; Apoptosis; Biocompatibility; Biotechnology; Bisphosphonates; Blocking antibodies; Care and treatment; Castration; Cells, Cultured; Clodronic acid; Cytotoxicity; Cytotoxicity, Immunologic - drug effects; Deprivation; Dihydrotestosterone; Dihydrotestosterone - pharmacology; Endocrinology; Gene expression; Humans; Immune response; Immune system; Immunotherapy; In vivo methods and tests; Liposomes; Macrophages; Macrophages - drug effects; Macrophages - immunology; Male; Metastases; Mice; Mice, Inbred C57BL; Monocytes; Peripheral blood; Physiological aspects; Prostate cancer; Prostatic Neoplasms - immunology; Prostatic Neoplasms - therapy; Receptors, Androgen - analysis; siRNA; Testing; Testosterone; Therapeutic applications; TNF-Related Apoptosis-Inducing Ligand - physiology; Toxicity; TRAIL protein; Tumor necrosis factor; South Korea
• ISSN: 1945-7170; 0013-7227; 1945-7170
• DOI: 10.1210/en.2019-00367

Although androgen deprivation therapy (ADT) and immunotherapy are potential treatment options in men with metastatic prostate cancer (CaP), androgen has conventionally been proposed to be a suppressor of the immune response. However, we herein report that DHT activates macrophages. When the murine macrophage cell line (RAW 264.7), human monocyte cell line (THP-1), and human peripheral blood monocytes were cultured with androgen-resistant CaP cell lines, DHT increased cytotoxicity of macrophages in a concentration-dependent manner. Further studies revealed that DHT induced M1 polarization and increased the expression levels of TNF-related apoptosis-inducing ligand (TRAIL) in macrophages and that this effect was abrogated when TRAIL was neutralized with a blocking antibody or small interfering RNA. Subsequent experiments demonstrated that induction of TRAIL expression was regulated by direct binding of androgen receptor to the TRAIL promoter region. Finally, an in vivo mouse study demonstrated that castration enhanced the growth of an androgen-resistant murine CaP tumor and that this protumorigenic effect of castration was blocked when macrophages were removed with clodronate liposomes. Collectively, these results demonstrate that DHT activates the cytotoxic activity of macrophages and suggest that immunotherapy may not be optimal when combined with ADT in CaP.