Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer
- 27 July 2011
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 108 (33), 13728-13733
- https://doi.org/10.1073/pnas.1107898108
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.Keywords
This publication has 33 references indexed in Scilit:
- Abiraterone and Increased Survival in Metastatic Prostate CancerThe New England Journal of Medicine, 2011
- The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its DisordersEndocrine Reviews, 2011
- Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 studyThe Lancet, 2010
- Phase II Study of Dutasteride for Recurrent Prostate Cancer During Androgen Deprivation TherapyJournal of Urology, 2009
- Maintenance of Intratumoral Androgens in Metastatic Prostate Cancer: A Mechanism for Castration-Resistant Tumor GrowthCancer Research, 2008
- Pre-receptor regulation of the androgen receptorMolecular and Cellular Endocrinology, 2008
- Increased Expression of Genes Converting Adrenal Androgens to Testosterone in Androgen-Independent Prostate CancerCancer Research, 2006
- Biology of Progressive, Castration-Resistant Prostate Cancer: Directed Therapies Targeting the Androgen-Receptor Signaling AxisJournal of Clinical Oncology, 2005
- Testosterone and Dihydrotestosterone Tissue Levels in Recurrent Prostate CancerClinical Cancer Research, 2005
- Finasteride, an inhibitor of 5 alpha-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasiaJournal of Clinical Endocrinology & Metabolism, 1992