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. Attached Files Name Description MIMEType Size Downloads 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, 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 Related Links Link Description Link to full-text (open access)     Unless expressly stated otherwise, the copyright for items in DRO is owned by the author, with all rights reserved. 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. Versions Version Filter Type Fri, 17 May 2019, 10:14:13 EST Fri, 17 May 2019, 10:14:58 EST Sat, 18 May 2019, 05:01:47 EST Mon, 20 May 2019, 08:11:04 EST Sat, 16 Jan 2021, 05:01:34 EST Wed, 17 Feb 2021, 12:30:42 EST Wed, 17 Feb 2021, 12:31:52 EST Wed, 17 Feb 2021, 15:02:40 EST Filtered Full Citation counts:   Cited 41 times in TR Web of Science Cited 0 times in Scopus Search Google Scholar Access Statistics: 17 Abstract Views, 0 File Downloads  -  Detailed Statistics Created: Fri, 17 May 2019, 10:14:58 EST

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.