ZIP9 Is a Druggable Determinant of Sex Differences in Melanoma.
Cancer Res
; 81(23): 5991-6003, 2021 12 01.
Article
em En
| MEDLINE
| ID: mdl-34706862
ABSTRACT
Melanoma and most other cancers occur more frequently and have worse prognosis in males compared with females. Although sex steroids are thought to be involved, classical androgen and estrogen receptors are not detectable in most melanomas. Here we show that testosterone promotes melanoma proliferation by activating ZIP9 (SLC39A9), a zinc transporter that is widely expressed in human melanoma but not intentionally targeted by available therapeutics. This testosterone activity required an influx of zinc, activation of MAPK, and nuclear translocation of YAP. FDA-approved inhibitors of the classical androgen receptor also inhibited ZIP9, thereby antagonizing the protumorigenic effects of testosterone in melanoma. In male mice, androgen receptor inhibitors suppressed growth of ZIP9-expressing melanomas but had no effect on isogenic melanomas lacking ZIP9 or on melanomas in females. These data suggest that ZIP9 might be effectively targeted in melanoma and other cancers by repurposing androgen receptor inhibitors that are currently approved only for prostate cancer. SIGNIFICANCE:
Testosterone signaling through ZIP9 mediates some of the sex differences in melanoma, and drugs that target AR can be repurposed to block ZIP9 and inhibit melanoma in males.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Testosterona
/
Receptores Androgênicos
/
Proteínas de Transporte de Cátions
/
Antagonistas de Receptores de Andrógenos
/
Melanoma
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Cancer Res
Ano de publicação:
2021
Tipo de documento:
Article