title: Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer.
abstract: Androgen deprivation therapy is the frontline treatment for metastatic prostate cancer; however, because the majority of cases of advanced prostate cancer progress to castration-resistant prostate cancer (CRPC), there is a considerable need to better understand the synthesis of intratumoral concentrations of the androgen receptor (AR) agonist, 5α-dihydrotestosterone (DHT) in CRPC. In a recent article in the Proceedings of the National Academy of Sciences, Chang et al. show that, contrary to widely held assumptions, the dominant pathway to DHT synthesis does not involve testosterone as a precursor to DHT, but instead involves the conversion of Δ ( 4) -androstenedione (AD) to 5α-dione (AD→5α-dione→DHT) by the steroid-5α-reductase isoenzyme 1 (SRD5A1). The authors show that it is this alternative pathway that drives the progression of CRPC, and they confirm these findings in six established human prostate cancer cell lines as well as in the metastatic tumors from two patients with CRPC. Such findings open the door to new areas of research and to the development of new therapeutic targets in CRPC.
authors.affiliation: Molecular Pharmacology Section, Medical Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Tessa J
authors.initials: TJ
authors.lastname: Campbell
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Tindall
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
mesh_terms: D013196:Dihydrotestosterone / Q000378:metabolism*; D018450:Disease Progression; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D011944:Receptors, Androgen / Q000378:metabolism*; D013739:Testosterone / Q000378:metabolism
chemical_list: D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D013739:Testosterone