BMX controls 3[beta]HSD1 and sex steroid biosynthesis in cancer

Prostate cancer is highly dependent on androgens and the androgen receptor (AR). Hormonal therapies inhibit gonadal testosterone production, block extragonadal androgen biosynthesis, or directly antagonize AR. Resistance to medical castration occurs as castration-resistant prostate cancer (CRPC) and...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of clinical investigation 2023-01, Vol.133 (2)
Main Authors: Li, Xiuxiu, Berk, Michael, Goins, Christopher, Alyamani, Mohammad, Chung, Yoon-Mi, Wang, Chenyao, Patel, Monaben, Rathi, Nityam, Zhu, Ziqi, Willard, Belinda, Stauffer, Shaun, Klein, Eric, Sharifi, Nima
Format: Article
Language:English
Subjects:
Allelomorphism
Androgens
Biosynthesis
Cancer
Development and progression
Enzymes
Estrogen
Genetic aspects
Health aspects
Oncology, Experimental
Phosphorylation
Physiological aspects
Prostate cancer
Protein tyrosine kinase
Scientific equipment and supplies industry
Testosterone
Tyrosine
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Prostate cancer is highly dependent on androgens and the androgen receptor (AR). Hormonal therapies inhibit gonadal testosterone production, block extragonadal androgen biosynthesis, or directly antagonize AR. Resistance to medical castration occurs as castration-resistant prostate cancer (CRPC) and is driven by reactivation of the androgen-AR axis. 3[beta]-hydroxysteroid dehydrogenase-1 (3[beta]HSD1) serves as the rate- limiting step for potent androgen synthesis from extragonadal precursors, thereby stimulating CRPC. Genetic evidence in men demonstrates the role of 3[beta]HSD1 in driving CRPC. In postmenopausal women, 3[beta]HSD1 is required for synthesis of aromatase substrates and plays an essential role in breast cancer. Therefore, 3[beta]HSD1 lies at a critical junction for the synthesis of androgens and estrogens, and this metabolic flux is regulated through germline-inherited mechanisms. We show that phosphorylation of tyrosine 344 (Y344) occurs and is required for 3[beta]HSD1 cellular activity and generation of [[DELTA].sup.4], 3-keto-substrates of 5[alpha]- reductase and aromatase, including in patient tissues. BMX directly interacts with 3[beta]HSD1 and is necessary for enzyme phosphorylation and androgen biosynthesis. In vivo blockade of 3[beta]HSD1 Y344 phosphorylation inhibits CRPC. These findings identify what we believe to be new hormonal therapy pharmacologic vulnerabilities for sex-steroid dependent cancers.
ISSN:0021-9738
DOI:10.1172/JCI163498