ArticleProceedings of the National Academy of Sciences of the United States of America2011
Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 184 papers.
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Who cites it
184 citing papers in PubMed, 336 citations in OpenAlex.
- Loss ofJCO precision oncology · 2021Trial
- Trial
- A Phase II Trial of Abiraterone Combined with Dutasteride for Men with Metastatic Castration-Resistant Prostate Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2017Trial
- Trial
- Safety, tolerability and anti-tumour activity of the androgen biosynthesis inhibitor ASP9521 in patients with metastatic castration-resistant prostate cancer: multi-centre phase I/II study.Investigational new drugs · 2014Trial
- Development, validation and application of a stable isotope dilution liquid chromatography electrospray ionization/selected reaction monitoring/mass spectrometry (SID-LC/ESI/SRM/MS) method for quantification of keto-androgens in human serum.The Journal of steroid biochemistry and molecular biology · 2013Trial
- Trial
- Steroid 5α-reductases in the brain: From neurosteroidogenesis to therapeutic implications.Frontiers in neuroendocrinology · 2026Review
- Serendipity, steroids and science.The Journal of steroid biochemistry and molecular biology · 2026Review
- Spatial localization and pharmacodynamic assessment of intracrine androgen metabolism in CRPC xenograft tumor tissues upon active vitamin D treatment.Analytical and bioanalytical chemistry · 2026Article
- Human SRD5A1 as a case of gene expression indel-resistance in triple-coding region.Genome biology · 2026Article
- Testosterone and cancers: biological functions, molecular mechanisms and therapy.Molecular cancer · 2026Review
- SRD5A2 and emerging therapies in androgen-driven disorders.Nature reviews. Urology · 2026Review
- Evolving Treatments and Resistance Mechanisms in Prostate Cancer Therapeutics.ACS pharmacology & translational science · 2026Review
- Androgen metabolism in prostate cancer: recent advances.Endocrinology · 2026Review
- Noncanonical functions of UGT2B17 promote castration-resistant prostate cancer progression.The Journal of clinical investigation · 2026Article
- Unveiling the potential targets and mechanisms of DEHP/BPA exposure on PCOS: insights from network toxicology and molecular docking.Journal of ovarian research · 2025Article
- NASP implication in the androgen receptor associated with castration resistance in prostate cancer.Cell communication and signaling : CCS · 2025Article
- Radioactive Tracing of Testosterone Reveals Minimal Formation of 5α-DHT in SGBS Cells and Human Primary Adipocytes.Journal of the Endocrine Society · 2025Article
- HSD3B1, prostate cancer mortality and modifiable outcomes.Nature reviews. Urology · 2025Review
124 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.