RT Journal Article
SR Electronic
T1 Testosterone signaling through ZIP9 renders melanoma more aggressive in males than in females
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.03.12.989160
DO 10.1101/2020.03.12.989160
A1 Cristina Aguirre-Portolés
A1 Riley Payne
A1 Aspen Trautz
A1 J. Kevin Foskett
A1 Christopher A. Natale
A1 Todd W. Ridky
YR 2020
UL http://biorxiv.org/content/early/2020/04/21/2020.03.12.989160.abstract
AB Melanoma and most other cancers occur more frequently, and have worse prognosis, in males compared with females. Though sex steroids are thought to be involved, melanoma lacks classical androgen and estrogen receptors. Here we show that testosterone promotes melanoma proliferation by activating ZIP9 (SLC39A9), a zinc transporter that is not intentionally targeted by available therapeutics. This activity requires zinc influx, MAPK activation and YAP1 nuclear translocation. We demonstrate that inhibitors of the classical androgen receptor, also inhibit ZIP9, and thereby antagonize the pro-tumorigenic 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, nor 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.Summary Androgen receptor inhibitors for prostate cancer also block the zinc transporter ZIP9, and thereby inhibit melanoma in males.Competing Interest StatementC.A.P., C.A.N., and T.W.R., and are inventors on a provisional patent held by the University of Pennsylvania related to this work.