Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8852, USA.
Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):13728-33. doi: 10.1073/pnas.1107898108. Epub 2011 Jul 27.
In the majority of cases, advanced prostate cancer responds initially to androgen deprivation therapy by depletion of gonadal testosterone. The response is usually transient, and metastatic tumors almost invariably eventually progress as castration-resistant prostate cancer (CRPC). The development of CRPC is dependent upon the intratumoral generation of the potent androgen, dihydrotestosterone (DHT), from adrenal precursor steroids. Progression to CRPC is accompanied by increased expression of steroid-5α-reductase isoenzyme-1 (SRD5A1) over SRD5A2, which is otherwise the dominant isoenzyme expressed in the prostate. DHT synthesis in CRPC is widely assumed to require 5α-reduction of testosterone as the obligate precursor, and the increased expression of SRD5A1 is thought to reflect its role in converting testosterone to DHT. Here, we show that the dominant route of DHT synthesis in CRPC bypasses testosterone, and instead requires 5α-reduction of androstenedione by SRD5A1 to 5α-androstanedione, which is then converted to DHT. This alternative pathway is operational and dominant in both human CRPC cell lines and fresh tissue obtained from human tumor metastases. Moreover, CRPC growth in mouse xenograft models is dependent upon this pathway, as well as expression of SRD5A1. These findings reframe the fundamental metabolic pathway that drives CRPC progression, and shed light on the development of new therapeutic strategies.
在大多数情况下，晚期前列腺癌最初通过耗尽性腺睾丸激素对雄激素剥夺疗法有反应。这种反应通常是短暂的，转移性肿瘤几乎总是最终发展为去势抵抗性前列腺癌（CRPC）。CRPC 的发展取决于肾上腺前体类固醇在肿瘤内产生强效雄激素二氢睾酮（DHT）。向 CRPC 的进展伴随着甾体 5α-还原酶同工酶-1（SRD5A1）相对于 SRD5A2 的表达增加，而 SRD5A2 是前列腺中表达的主要同工酶。CRPC 中的 DHT 合成广泛假定需要 5α-还原睾酮作为必需前体，并且 SRD5A1 的表达增加被认为反映了其将睾酮转化为 DHT 的作用。在这里，我们表明，CRPC 中 DHT 合成的主要途径绕过了睾酮，而是需要 SRD5A1 将雄烯二酮 5α-还原为 5α-雄烷二酮，然后将其转化为 DHT。这种替代途径在人 CRPC 细胞系和人肿瘤转移获得的新鲜组织中均有效且占主导地位。此外，CRPC 在小鼠异种移植模型中的生长依赖于该途径以及 SRD5A1 的表达。这些发现重新构建了驱动 CRPC 进展的基本代谢途径，并为新的治疗策略的发展提供了线索。
