A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer.
Cell
; 154(5): 1074-1084, 2013 Aug 29.
Article
en En
| MEDLINE
| ID: mdl-23993097
ABSTRACT
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 3ß-hydroxysteroid dehydrogenase type 1 (3ßHSD1), 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 3ßHSD1 is a valid target for the treatment of CRPC.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias de la Próstata
/
Dihidrotestosterona
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Regulación Neoplásica de la Expresión Génica
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3-Hidroxiesteroide Deshidrogenasas
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Cell
Año:
2013
Tipo del documento:
Article