2. Academic Validation
  3. Targeted suppression of AR-V7 using PIP5K1α inhibitor overcomes enzalutamide resistance in prostate cancer cells

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

  • Oncotarget. 2016 Sep 27;7(39):63065-63081. doi: 10.18632/oncotarget.11757.
Martuza Sarwar 1,  Julius Semenas 1 2,  Regina Miftakhova 1 3 2,  Athanasios Simoulis 4,  Brian Robinson 5,  Anette Gjörloff Wingren 6,  Nigel P Mongan 7,  David M Heery 8,  Heather Johnsson 9,  Per-Anders Abrahamsson 10,  Nishtman Dizeyi 10,  Jun Luo 11,  Jenny L Persson 1 2
Affiliations

Affiliations

  • 1 Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden.
  • 2 Department of Molecular Biology, Umeå University, Umeå, Sweden.
  • 3 Department of Genetics, Kazan Federal University, Kazan, Russia.
  • 4 Department of Clinical Pathology and Cytology, Skåne University Hospital, Malmö, Sweden.
  • 5 Department of Pathology, Weill Cornell Medical College, New York, NY, USA.
  • 6 Faculty of Health and Society, Department of Biomedical Science, Malmö University, Malmö, Sweden.
  • 7 Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Sciences, University of Nottingham, Nottingham, United Kingdom.
  • 8 School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
  • 9 Department of Bio-Diagnosis, Beijing Institute of Basic Medical Sciences, Beijing, China.
  • 10 Division of Clinical Urology, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden.
  • 11 Department of Urology, the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
PMID: 27588408 DOI: 10.18632/oncotarget.11757
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.

Keywords

AR-V7; PIP5K1α; enzalutamide resistance; lipid kinase inhibitor; prostate cancer metastasis.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16937
    99.97%, PIP5K1α Inhibitor