期刊
CELL
卷 154, 期 5, 页码 1074-1084出版社
CELL PRESS
DOI: 10.1016/j.cell.2013.07.029
关键词
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资金
- Howard Hughes Medical Institute
- Prostate Cancer Foundation
- American Cancer Society [12-038-01-CCE]
- U.S. Army Medical Research and Materiel Command [PC080193]
- National Cancer Institute [1R01CA168899, 1R01CA172382-01]
- [PO1-CA85859]
- [PC093509]
- [P01CA163227]
- [P50CA097186]
Growth of prostate cancer cells is dependent upon androgen stimulation of the androgen receptor (AR). Dihydrotestosterone (DHT), the most potent androgen, is usually synthesized in the prostate from testosterone secreted by the testis. Following chemical or surgical castration, prostate cancers usually shrink owing to testosterone deprivation. However, tumors often recur, forming castration-resistant prostate cancer (CRPC). Here, we show that CRPC sometimes expresses a gain-of-stability mutation that leads to a gain-of-function in 3 beta-hydroxysteroid dehydrogenase type 1 (3 beta HSD1), which catalyzes the initial rate-limiting step in conversion of the adrenal-derived steroid dehydroepiandrosterone to DHT. The mutation (N367T) does not affect catalytic function, but it renders the enzyme resistant to ubiquitination and degradation, leading to profound accumulation. Whereas dehydroepiandrosterone conversion to DHT is usually very limited, expression of 367T accelerates this conversion and provides the DHT necessary to activate the AR. We suggest that 3 beta HSD1 is a valid target for the treatment of CRPC.
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