Targeted suppression of AR-V7 using PIP5K1α inhibitor overcomes enzalutamide resistance in prostate cancer cells
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Martuza Sarwar1, Julius Semenas1,11, Regina Miftakhova1,2,11, Athanasios Simoulis3, Brian Robinson4, Anette Gjörloff Wingren5, Nigel P. Mongan6, David M. Heery7, Heather Johnsson8, Per-Anders Abrahamsson9, Nishtman Dizeyi9, Jun Luo10, and Jenny L. Persson1,11
1 Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden
2 Department of Genetics, Kazan Federal University, Kazan, Russia
3 Department of Clinical Pathology and Cytology, Skåne University Hospital, Malmö, Sweden
4 Department of Pathology, Weill Cornell Medical College, New York, NY, USA
5 Faculty of Health and Society, Department of Biomedical Science, Malmö University, Malmö, Sweden
6 Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Sciences, University of Nottingham, Nottingham, United Kingdom
7 School of Pharmacy, University of Nottingham, Nottingham, United Kingdom
8 Department of Bio-Diagnosis, Beijing Institute of Basic Medical Sciences, Beijing, China
9 Division of Clinical Urology, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden
10 Department of Urology, the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
11 Department of Molecular Biology, Umeå University, Sweden
Jenny L. Persson, email:
Keywords: prostate cancer metastasis, enzalutamide resistance, lipid kinase inhibitor, AR-V7, PIP5K1α
Received: July 28, 2016 Accepted: August 20, 2016 Published: August 31, 2016
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.
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