Martuza Sarwar
Targeted suppression of AR-V7 using PIP5K1? inhibitor overcomes enzalutamide resistance in prostate cancer cells
Sarwar, Martuza; Semenas, Julius; Miftakhova, Regina; Simoulis, Athanasios; Robinson, Brian; Wingren, Anette Gj�rloff; Mongan, Nigel P.; Heery, David M.; Johnsson, Heather; Abrahamsson, Per-Anders; Dizeyi, Nishtman; Luo, Jun; Persson, Jenny L.
Authors
Julius Semenas
Regina Miftakhova
Athanasios Simoulis
Brian Robinson
Anette Gj�rloff Wingren
NIGEL MONGAN nigel.mongan@nottingham.ac.uk
Professor of Oncology
DAVID HEERY david.heery@nottingham.ac.uk
Professor of Eucaryotic Gene Regulation
Heather Johnsson
Per-Anders Abrahamsson
Nishtman Dizeyi
Jun Luo
Jenny L. Persson
Abstract
One mechanism of resistance of prostate cancer (PCa) to enzalutamide (MDV3100) treatment is the increased expression of AR variants lacking the ligand binding-domain, the best characterized of which is AR-V7. We have previously reported that Phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Ka), is a lipid kinase that links to CDK1 and AR pathways. The discovery of PIP5Ka inhibitor highlight the potential of PIP5K1? as a drug target in PCa. In this study, we show that AR-V7 expression positively correlates with PIP5K1? in tumor specimens from PCa patients. Overexpression of AR-V7 increases PIP5K1?, promotes rapid growth of PCa in xenograft mice, whereas inhibition of PIP5K1? by its inhibitor ISA-2011B suppresses the growth and invasiveness of xenograft tumors overexpressing AR-V7. PIP5K1? is a key co-factor for both AR-V7 and AR, which are present as protein-protein complexes predominantly in the nucleus of PCa cells. In addition, PIP5K1? and CDK1 influence AR-V7 expression also through AKT-associated mechanism dependent on PTEN-status. ISA-2011B disrupts protein stabilization of AR-V7 which is dependent on PIP5K1?, leading to suppression of invasive growth of AR-V7-high tumors in xenograft mice. Our study suggests that combination of enzalutamide and PIP5K1? may have a significant impact on refining therapeutic strategies to circumvent resistance to antiandrogen therapies.
Citation
Sarwar, M., Semenas, J., Miftakhova, R., Simoulis, A., Robinson, B., Wingren, A. G., …Persson, J. L. (2016). Targeted suppression of AR-V7 using PIP5K1α inhibitor overcomes enzalutamide resistance in prostate cancer cells. Oncotarget, 7(39), 63065-63081. https://doi.org/10.18632/oncotarget.11757
Journal Article Type | Article |
---|---|
Acceptance Date | Aug 20, 2016 |
Online Publication Date | Aug 31, 2016 |
Publication Date | Sep 27, 2016 |
Deposit Date | Sep 15, 2016 |
Publicly Available Date | Sep 15, 2016 |
Journal | Oncotarget |
Electronic ISSN | 1949-2553 |
Publisher | Impact Journals |
Peer Reviewed | Peer Reviewed |
Volume | 7 |
Issue | 39 |
Pages | 63065-63081 |
DOI | https://doi.org/10.18632/oncotarget.11757 |
Keywords | Prostate Cancer Metastasis, Enzalutamide Resistance, Lipid Kinase Inhibitor, AR-V7, PIP5K1? |
Public URL | https://nottingham-repository.worktribe.com/output/803845 |
Publisher URL | http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=11757 |
Files
2016_Oncotarget_ARv7reprint.pdf
(13.9 Mb)
PDF
Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0
You might also like
PIP5K1α is Required for Promoting Tumor Progression in Castration-Resistant Prostate Cancer
(2022)
Journal Article
Invasive Lobular Breast Cancer as a Distinct Disease: Implications for Therapeutic Strategy
(2019)
Journal Article
Downloadable Citations
About Repository@Nottingham
Administrator e-mail: digital-library-support@nottingham.ac.uk
This application uses the following open-source libraries:
SheetJS Community Edition
Apache License Version 2.0 (http://www.apache.org/licenses/)
PDF.js
Apache License Version 2.0 (http://www.apache.org/licenses/)
Font Awesome
SIL OFL 1.1 (http://scripts.sil.org/OFL)
MIT License (http://opensource.org/licenses/mit-license.html)
CC BY 3.0 ( http://creativecommons.org/licenses/by/3.0/)
Powered by Worktribe © 2024
Advanced Search