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Aberrant corticosteroid metabolism in tumor cells enables GR takeover in enzalutamide resistant prostate cancer

Li, J, Alyamani, M, Zhang, A, Chang, K-H, Berk, Michael, Li, Z, Zhu, Z, Petro, M, Magi-Galluzzi, C, Taplin, M-E, Garcia, JA, Courtney, K, Klein, EA and Sharifi, N 2017, Aberrant corticosteroid metabolism in tumor cells enables GR takeover in enzalutamide resistant prostate cancer, eLIFE, vol. 6, pp. 1-17, doi: 10.7554/eLife.20183.

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Title Aberrant corticosteroid metabolism in tumor cells enables GR takeover in enzalutamide resistant prostate cancer
Author(s) Li, J
Alyamani, M
Zhang, A
Chang, K-H
Berk, MichaelORCID iD for Berk, Michael orcid.org/0000-0002-5554-6946
Li, Z
Zhu, Z
Petro, M
Magi-Galluzzi, C
Taplin, M-E
Garcia, JA
Courtney, K
Klein, EA
Sharifi, N
Journal name eLIFE
Volume number 6
Article ID e20183
Start page 1
End page 17
Total pages 17
Publisher eLife Sciences Publications
Place of publication Cambridge, Eng.
Publication date 2017-02-13
ISSN 2050-084X
2050-084X
Keyword(s) Science & Technology
Life Sciences & Biomedicine
Biology
Life Sciences & Biomedicine - Other Topics
ANDROGEN-RECEPTOR
GLUCOCORTICOIDS
CHEMOTHERAPY
ABIRATERONE
ACTIVATION
THERAPY
ER
androgens
biochemistry
cancer biology
human
nuclear receptors
prostate cancer
treatment resistance
Summary Prostate cancer is driven by androgen stimulation of the androgen receptor (AR). The next-generation AR antagonist, enzalutamide, prolongs survival, but resistance and lethal disease eventually prevail. Emerging data suggest that the glucocorticoid receptor (GR) is upregulated in this context, stimulating expression of AR-target genes that permit continued growth despite AR blockade. However, countering this mechanism by administration of GR antagonists is problematic because GR is essential for life. We show that enzalutamide treatment in human models of prostate cancer and patient tissues is accompanied by a ubiquitin E3-ligase, AMFR, mediating loss of 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which otherwise inactivates cortisol, sustaining tumor cortisol concentrations to stimulate GR and enzalutamide resistance. Remarkably, reinstatement of 11β-HSD2 expression, or AMFR loss, reverses enzalutamide resistance in mouse xenograft tumors. Together, these findings reveal a surprising metabolic mechanism of enzalutamide resistance that may be targeted with a strategy that circumvents a requirement for systemic GR ablation.
Language eng
DOI 10.7554/eLife.20183
Indigenous content off
Field of Research 0601 Biochemistry and Cell Biology
HERDC Research category C1 Refereed article in a scholarly journal
Free to Read? Yes
Persistent URL http://hdl.handle.net/10536/DRO/DU:30121657

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
Open Access Collection
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.