二氢睾酮
前列腺癌
细胞毒性T细胞
雄激素受体
雄激素
内分泌学
内科学
癌症研究
单核细胞
细胞培养
免疫系统
雄激素剥夺疗法
生物
化学
医学
免疫学
癌症
体外
激素
生物化学
遗传学
作者
Geun Taek Lee,Jeong Hyun Kim,Seok Joo Kwon,Mark N. Stein,Jeong Hee Hong,Naoya Nagaya,Sachin Billakanti,Melina Minji Kim,Isaac Yi Kim,Isaac Yi Kim
标识
DOI:10.1210/en.2019-00367
摘要
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.
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