title: Targeted suppression of AR-V7 using PIP5K1α inhibitor overcomes enzalutamide resistance in prostate cancer cells.
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.
authors: Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden.
authors: Martuza
authors: M
authors: Sarwar
authors: Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden.|Department of Molecular Biology, Umeå University, Umeå, Sweden.
authors: Julius
authors: J
authors: Semenas
authors: Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden.|Department of Genetics, Kazan Federal University, Kazan, Russia.|Department of Molecular Biology, Umeå University, Umeå, Sweden.
authors: Regina
authors: R
authors: Miftakhova
authors: Department of Clinical Pathology and Cytology, Skåne University Hospital, Malmö, Sweden.
authors: Athanasios
authors: A
authors: Simoulis
authors: Department of Pathology, Weill Cornell Medical College, New York, NY, USA.
authors: Brian
authors: B
authors: Robinson
authors: Faculty of Health and Society, Department of Biomedical Science, Malmö University, Malmö, Sweden.
authors: Anette
authors: A
authors: Gjörloff Wingren
authors: Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Sciences, University of Nottingham, Nottingham, United Kingdom.
authors: Nigel P
authors: NP
authors: Mongan
authors: School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
authors: David M
authors: DM
authors: Heery
authors: Department of Bio-Diagnosis, Beijing Institute of Basic Medical Sciences, Beijing, China.
authors: Heather
authors: H
authors: Johnsson
authors: Division of Clinical Urology, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden.
authors: Per-Anders
authors: PA
authors: Abrahamsson
authors: Division of Clinical Urology, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden.
authors: Nishtman
authors: N
authors: Dizeyi
authors: Department of Urology, the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Jun
authors: J
authors: Luo
authors: Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden.|Department of Molecular Biology, Umeå University, Umeå, Sweden.
authors: Jenny L
authors: JL
authors: Persson
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001549:Benzamides; D049109:Cell Proliferation; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011467:Prostate / Q000378:metabolism; D011470:Prostatic Hyperplasia / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011944:Receptors, Androgen / Q000737:chemistry* / Q000235:genetics; D015398:Signal Transduction; D046888:Tissue Array Analysis
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D001549:Benzamides; D008055:Lipids; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide
keywords: AR-V7; PIP5K1α; enzalutamide resistance; lipid kinase inhibitor; prostate cancer metastasis