Targeting 3beta-HSD1 Phosphorylation to Reverse Prostate Cancer Hormone Therapy Resistance
Abstract
Prostate cancer is the most common malignancy in men and the second leading cause of cancer-related death in men in the United States. Androgen deprivation therapy (ADT) is the front-line treatment, but it eventually fails and disease almost always progresses as castration-resistant prostate cancer (CRPC). Nearly all prostate cancer deaths are due to CRPC. It has been demonstrated that intratumoral androgen synthesis is required to drive CRPC progression. The enzyme 3-hydroxysteroiddehydrogenase type 1 (3HSD1), which catalyzes the initial rate-limiting step in the conversion of the adrenal-derived steroid dehydroepiandrosterone to dihydrotestosterone (the most potent natural stimulus of the androgen receptor), is likely a critical enzymatic gatekeeper that confers on tumors the ability to harness adrenal androgens. Genetic evidence in men demonstrates the role of 3HSD1 in driving CRPC. In postmenopausal women, 3HSD1 is required for synthesis of aromatase substrates and plays an essential role in breast cancer. Therefore, 3HSD1 lies at the major decision point for synthesis of androgens vs. estrogens and where metabolic flux is also genetically regulated through germline inheritance. I have found that phosphorylation of Y344 occurs, is required for 3HSD1 cellular activity and generation of 4, 3-keto-substrates of 5reductase and aromatase, including in patient tissues. I also demonstrated BMX directly interacts with 3HSD1 and is necessary for enzyme phosphorylation and androgen biosynthesis. In vivo investigation showed that blockade of 3HSD1Y344 phosphorylation inhibits CRPC. These findings identify new hormonal therapy pharmacologic vulnerabilities for sex-steroid dependent cancers.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2023
- Accession Number
- AD1212444
Entities
People
- Xiuxiu Li