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Accession Number:

AD1155414

Title:

Targeting 3beta-HSD1 Phosphorylation to Reverse Prostate Cancer Hormone Therapy Resistance

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Report Date:

2021-10-01

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 3Beta-hydroxysteroiddehydrogenase type 1 (3BetaHSD1), 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. 3BetaHSD1 has been mechanistically linked to CRPC and is associated with prostate cancer resistance to ADT. Recently, we reported that a HSD3B1 germline variant regulates dueling abiraterone metabolite effects and affects prognosis. Protein phosphorylation is a reversible posttranslational modification mediated by kinases that modifies protein function. 3BetaHSD1 is critical to androgen synthesis and prostate cancer growth, but no functional phosphorylation sites have been identified. My preliminary studies show that in the LNCaP and C4-2 PCa cell lines, Compound C, an inhibitor of AMP-activated protein kinase (AMPK), inhibits 3BetaHSD1 activity without affecting its expression but decreases its phosphorylation, suggesting that phosphorylation of 3BetaHSD1 is important to its activity and that the regulatory kinase may be a potential treatment target. Therefore, I hypothesize that phosphorylation of3BetaHSD1 modifies its function and the functional phosphorylation or regulatory kinase promotes CRPC. If so, targeting the functional phosphorylation or kinase could be new strategy for CRPC treatment.

Pages:

10

File Size:

0.72MB

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Distribution Statement:

Approved For Public Release

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