Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
Mol Cell Endocrinol. 2019 Apr 15;486:79-88. doi: 10.1016/j.mce.2019.02.018. Epub 2019 Feb 23.
Adrenal androgens dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) are potential substrates for intracrine production of testosterone (T) and dihydrotestosterone (DHT), or directly to DHT, by prostate cancer (PCa) cells. Production of DHT from DHEAS and DHEA, and the role of steroid sulfatase (STS), were evaluated ex vivo using fresh human prostate tissue and in vitro using human PCa cell lines. STS was expressed in benign prostate tissue and PCa tissue. DHEAS at a physiological concentration was converted to DHT in prostate tissue and PCa cell lines, which was STS-dependent. DHEAS activation of androgen receptor (AR) and stimulation of PCa cell growth were STS-dependent. DHEA at a physiological concentration was not converted to DHT ex vivo and in vitro, but stimulated in vivo tumor growth of the human PCa cell line, VCaP, in castrated mice. The findings suggest that targeting metabolism of DHEAS and DHEA may enhance androgen deprivation therapy.
肾上腺雄激素脱氢表雄酮（DHEA）和硫酸脱氢表雄酮（DHEAS）是前列腺癌（PCa）细胞内源性产生睾酮（T）和二氢睾酮（DHT）的潜在底物，或者直接转化为 DHT。本研究采用新鲜人前列腺组织进行体外实验，使用人前列腺癌细胞系进行离体实验，评估了 DHEAS 和 DHEA 转化为 DHT 的情况，以及甾体硫酸酯酶（STS）的作用。STS 在良性前列腺组织和 PCa 组织中均有表达。在前列腺组织和 PCa 细胞系中，生理浓度的 DHEAS 可转化为 DHT，且这一过程依赖于 STS。DHEAS 激活雄激素受体（AR）并刺激 PCa 细胞生长，这一过程同样依赖于 STS。在离体和体外实验中，生理浓度的 DHEA 不能转化为 DHT，但能刺激去势小鼠体内人前列腺癌细胞系 VCaP 的肿瘤生长。这些发现表明，靶向 DHEAS 和 DHEA 的代谢可能增强雄激素剥夺疗法。
