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Targeted suppression of AR-V7 using PIP5K1 alpha inhibitor overcomes enzalutamide resistance in prostate cancer cells
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden.
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden; Department of Genetics, Kazan Federal University, Kazan, Russia.
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 39, 63065-63081 p.Article in journal (Refereed) Published
Abstract [en]

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 (PIP5K alpha), is a lipid kinase that links to CDK1 and AR pathways. The discovery of PIP5K alpha inhibitor highlight the potential of PIP5K1 alpha as a drug target in PCa. In this study, we show that AR-V7 expression positively correlates with PIP5K1 alpha in tumor specimens from PCa patients. Overexpression of AR-V7 increases PIP5K1 alpha, promotes rapid growth of PCa in xenograft mice, whereas inhibition of PIP5K1 alpha by its inhibitor ISA-2011B suppresses the growth and invasiveness of xenograft tumors overexpressing AR-V7. PIP5K1 alpha 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 alpha 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 alpha, leading to suppression of invasive growth of AR-V7-high tumors in xenograft mice. Our study suggests that combination of enzalutamide and PIP5K1 alpha may have a significant impact on refining therapeutic strategies to circumvent resistance to antiandrogen therapies.

Place, publisher, year, edition, pages
2016. Vol. 7, no 39, 63065-63081 p.
Keyword [en]
Prostate cancer metastasis, enzalutamide resistance, lipid kinase inhibitor, AR-V7, PIP5K1α
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-128475DOI: 10.18632/oncotarget.11757ISI: 000387167800020OAI: oai:DiVA.org:umu-128475DiVA: diva2:1056647
Available from: 2016-12-15 Created: 2016-12-05 Last updated: 2016-12-15Bibliographically approved

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Semenas, JuliusMiftakhova, ReginaPersson, Jenny L.
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