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Confirmatory Results

ZIP9 is a Druggable Determinant of Sex Differences in Melanoma

Cristina Aguirre-Portolés, Riley Payne, Aspen Trautz, J. Kevin Foskett, Christopher A. Natale, John T. Seykora, View ORCID ProfileTodd W. Ridky
doi: https://doi.org/10.1101/2020.03.12.989160
Cristina Aguirre-Portolés
1Department of Dermatology, Perelman School of Medicine, University of Pennsylvania
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Riley Payne
2Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. USA
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Aspen Trautz
1Department of Dermatology, Perelman School of Medicine, University of Pennsylvania
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J. Kevin Foskett
2Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. USA
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Christopher A. Natale
1Department of Dermatology, Perelman School of Medicine, University of Pennsylvania
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John T. Seykora
1Department of Dermatology, Perelman School of Medicine, University of Pennsylvania
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Todd W. Ridky
1Department of Dermatology, Perelman School of Medicine, University of Pennsylvania
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  • ORCID record for Todd W. Ridky
  • For correspondence: ridky@pennmedicine.upenn.edu
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Abstract

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, 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 not intentionally targeted by available therapeutics, but is widely expressed in human melanoma. This testosterone activity requires zinc influx, MAPK activation and YAP1 nuclear translocation. We demonstrate that FDA approved 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.

Competing Interest Statement

C.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.

Footnotes

  • Conflict of interest: T.W.R., C.A.N and C.A.P. are inventors on a provisional patent held by the University of Pennsylvania related to this work.

  • New confirmatory data Clarified text and data

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 07, 2021.
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ZIP9 is a Druggable Determinant of Sex Differences in Melanoma
Cristina Aguirre-Portolés, Riley Payne, Aspen Trautz, J. Kevin Foskett, Christopher A. Natale, John T. Seykora, Todd W. Ridky
bioRxiv 2020.03.12.989160; doi: https://doi.org/10.1101/2020.03.12.989160
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ZIP9 is a Druggable Determinant of Sex Differences in Melanoma
Cristina Aguirre-Portolés, Riley Payne, Aspen Trautz, J. Kevin Foskett, Christopher A. Natale, John T. Seykora, Todd W. Ridky
bioRxiv 2020.03.12.989160; doi: https://doi.org/10.1101/2020.03.12.989160

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