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Targeted suppression of AR-V7 using PIP5K1α inhibitor overcomes enzalutamide resistance in prostate cancer cells

Sarwar, Martuza; Semenas, Julius; Miftakhova, Regina; Simoulis, Athanasios; Robinson, Brian; Wingren, Anette Gjörloff; Mongan, Nigel P.; Heery, David M.; Johnsson, Heather; Abrahamsson, Per-Anders; Dizeyi, Nishtman; Luo, Jun; Persson, Jenny L.

Authors

Martuza Sarwar

Julius Semenas

Regina Miftakhova

Athanasios Simoulis

Brian Robinson

Anette Gjörloff Wingren

DAVID HEERY david.heery@nottingham.ac.uk
Professor of Eucaryoticgene 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 (PIP5Kα), is a lipid kinase that links to CDK1 and AR pathways. The discovery of PIP5Kα inhibitor highlight the potential of PIP5K1α as a drug target in PCa. In this study, we show that AR-V7 expression positively correlates with PIP5K1α in tumor specimens from PCa patients. Overexpression of AR-V7 increases PIP5K1α, promotes rapid growth of PCa in xenograft mice, whereas inhibition of PIP5K1α by its inhibitor ISA-2011B suppresses the growth and invasiveness of xenograft tumors overexpressing AR-V7. PIP5K1α 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, PIP5K1α 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 PIP5K1α, leading to suppression of invasive growth of AR-V7-high tumors in xenograft mice. Our study suggests that combination of enzalutamide and PIP5K1α 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 Aug 31, 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, PIP5K1α
Public URL http://eprints.nottingham.ac.uk/id/eprint/36657
Publisher URL http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=11757
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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