title: Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer.
abstract: 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.
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8852, USA.
authors.forename: Kai-Hsiung
authors.initials: KH
authors.lastname: Chang
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.forename: Mahboubeh
authors.initials: M
authors.lastname: Papari-Zareei
authors.forename: Lori
authors.initials: L
authors.lastname: Watumull
authors.forename: Yan Daniel
authors.initials: YD
authors.lastname: Zhao
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Auchus
authors.forename: Nima
authors.initials: N
authors.lastname: Sharifi
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism*; D000818:Animals; D002369:Castration; D013196:Dihydrotestosterone / Q000378:metabolism*; D018450:Disease Progression; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D051379:Mice; D011471:Prostatic Neoplasms / Q000378:metabolism*; D013739:Testosterone; D014183:Transplantation, Heterologous
chemical_list: D008565:Membrane Proteins; D013196:Dihydrotestosterone; D013739:Testosterone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548467:SRD5A1 protein, human; C548468:SRD5A2 protein, human; C518406:Srd5a1 protein, mouse