雄激素合成关键酶AKR1C3：小檗碱防治去势抵抗性前列腺癌的新靶标

The acquired ability of intratumoral steroidogenesis in prostate cancer cell is the key factor for prostate cancer progression to castration resistant prostate cancer (CRPC). Aldo-keto reductase 3 (AKR1C3) is the key enzyme for transforming low active hormone precursor to highly active testosterone and dihydrotestosterone in prostate cancer cell. Our previous study found that the expression level of AKR1C3 was closely correlated with Gleason grade of prostate cancer, and the protein expression of AKR1C3 increased with the progress of the bearing transplanted prostate cancer in nude mouse with orchectomy progression to CRPC. Therefore, screening and developing AKR1C3 inhibitor becomes a new strategy for the prevention and treatment of CRPC. We also found that Berberine (BBR) could bind with enzyme active center of AKR1C3 utilizing computer molecule simulation technique. In addition, BBR could inhibit the production of testosterone in C4-2B prostate cancer cell line and prolong the latent period of prostate cancer progression to CRPC in castrated nude mice beared LNCaP transplanted tumor. Based on these results, this project intend to further investigate the function of AKR1C3 in the progression of CRPC and the effect and molecular mechanism of BBR in preventing and treating CRPC by decreasing the production of androgen in prostate cancer cells, using AKR1C3 over-expressional cell line and nude mouse subcutaneous transplantation tumor model. Our study would provide experimental basis for the prophylaxis and treatment of CRPC using BBR, as well as the new strategy for the clinical therapy of CRPC.

前列腺癌细胞自身获得合成雄激素的能力是其进展为去势抵抗性前列腺癌（CRPC）的关键因素，其中醛-酮降解酶3 (AKR1C3)是癌细胞利用低活性激素前体转化高活性睾酮和双氢睾酮最后阶段的关键酶。我们前期研究发现AKR1C3表达水平与人前列腺癌标本的Gleason分级呈正相关，裸鼠皮下移植瘤进展为CRPC后AKR1C3表达上调。因此，筛选靶向AKR1C3抑制剂是防治CRPC的新策略。我们利用计算机分子模拟筛选出小檗碱（BBR）与AKR1C3的结合能力强，体外可降低细胞内睾酮生成，延长了裸鼠皮下移植瘤进展为CRPC的潜伏期。本项目拟利用AKR1C3过表达细胞系以及去势裸鼠原位移植瘤模型，进一步揭示AKR1C3在CRPC发生发展中的作用，阐明BBR体内外靶向抑制AKR1C3，降低前列腺癌细胞内雄激素生成的作用和分子机制，为利用BBR防治CRPC提供实验依据，为前列腺肿瘤的临床治疗提供新策略。

前列腺癌细胞自身获得合成雄激素的能力是其进展为去势抵抗性前列腺癌（CRPC）的重要机制。醛酮降解酶3（AKR1C3）是前列腺癌细胞利用胆固醇为原料，自身合成睾酮和双氢睾酮最后两步的关键酶，因此，靶向AKR1C3，抑制雄激素的自身合成，可能是防治CRPC的新策略。本项目利用人前列腺癌穿刺样品、前列腺癌细胞系和去势裸鼠移植瘤模型，揭示了AKR1C3在CRPC发生和发展中具有重要作用，提出AKR1C3可作为CRPC的治疗靶点。并进一步明确了小檗碱（BBR）具有抑制AKR1C3的作用，阐明了BBR在体内外可通过靶向抑制AKR1C3的活性，降低前列腺癌细胞内雄激素生成，从而抑制AR信号通路的活化，最终达到防治CRPC的目的。本研究为利用BBR防治CRPC提供了实验依据，为前列腺肿瘤的临床治疗提供了新的策略。