Department of Urinary Surgery, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, PR China.
Endocrine. 2022 Feb;75(2):635-645. doi: 10.1007/s12020-021-02907-7. Epub 2021 Oct 28.
Evodiamine (EVO) is a bioactive alkaloid that exerts antitumor activity in various cancers, including prostate cancer (PCa). In this paper, we further investigated the molecular mechanisms underlying the anti-PCa effect of evodiamine. In the present study, cell proliferation, colony formation, migration, and invasion were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, and transwell assays, respectively. Animal studies were used to evaluate the effect of evodiamine on the tumorigenicity of LNCaP cells in vivo. The expression levels of steroid receptor coactivator (Src), androgene receptor (AR), and prostate-specific antigen (PSA) were detected by western blot, quantitative real-time PCR (qRT-PCR) or ELISA assay. Association between Src and AR was examined by Co-Immunoprecipitation (CoIP). The impact of evodiamine on AR-mediated transcriptional activity was confirmed by dual-luciferase reporter assay. The results showed that evodiamine reduced LNCaP and 22Rv1 cell proliferation, colony formation, migration, and invasion induced by dihydrotestosterone (DHT) in vitro, as well as diminished tumor growth in vivo. Mechanistically, evodiamine directly targeted Src and reduced DHT-induced Src activation. Moreover, the restoration of Src activation abolished evodiamine-mediated suppression of proliferation, migration, and invasion of DHT-treated LNCaP and 22Rv1 cells. Furthermore, evodiamine inhibited DHT-induced AR transcriptional activity through targeting Src. As a conclusion, our findings demonstrate the antitumor property of evodiamine in PCa by blocking AR transcriptional activity through targeting Src and provide a rationale for developing evodiamine as a promising antitumor agent against PCa.
吴茱萸碱（EVO）是一种具有生物活性的生物碱，在多种癌症中具有抗肿瘤活性，包括前列腺癌（PCa）。在本文中，我们进一步研究了吴茱萸碱抑制前列腺癌细胞的分子机制。在本研究中，通过 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）、集落形成和 Transwell 分析分别评估细胞增殖、集落形成、迁移和侵袭。动物研究用于评估吴茱萸碱对 LNCaP 细胞体内致瘤性的影响。通过 Western blot、定量实时 PCR（qRT-PCR）或 ELISA 检测类固醇受体共激活剂（Src）、雄激素受体（AR）和前列腺特异性抗原（PSA）的表达水平。通过免疫共沉淀（CoIP）检测 Src 和 AR 之间的关联。通过双荧光素酶报告基因检测证实了吴茱萸碱对 AR 介导的转录活性的影响。结果表明，吴茱萸碱减少了体外二氢睾酮（DHT）诱导的 LNCaP 和 22Rv1 细胞增殖、集落形成、迁移和侵袭，以及体内肿瘤生长。机制上，吴茱萸碱直接靶向 Src 并减少 DHT 诱导的 Src 激活。此外，Src 激活的恢复消除了吴茱萸碱对 DHT 处理的 LNCaP 和 22Rv1 细胞增殖、迁移和侵袭的抑制作用。此外，吴茱萸碱通过靶向 Src 抑制 DHT 诱导的 AR 转录活性。总之，我们的研究结果表明，吴茱萸碱通过阻断 AR 转录活性抑制前列腺癌，为开发吴茱萸碱作为治疗前列腺癌的有前途的抗肿瘤药物提供了依据。
