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  • Sarwar, MartuzaLund University,Lunds universitet,Experimentell cancerforskning, Malmö,Forskargrupper vid Lunds universitet,Experimental Cancer Research, Malmö,Lund University Research Groups (author)

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

  • Article/chapterEnglish2016

Publisher, publication year, extent ...

  • 2016-08-31
  • Impact Journals,2016
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:mau-5415
  • https://urn.kb.se/resolve?urn=urn:nbn:se:mau:diva-5415URI
  • https://doi.org/10.18632/oncotarget.11757DOI
  • https://lup.lub.lu.se/record/c6f4b8b1-8a89-4df0-9e06-368b57eb49beURI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Semenas, JuliusUmeå University,Lund University,Lunds universitet,Experimentell cancerforskning, Malmö,Forskargrupper vid Lunds universitet,Experimental Cancer Research, Malmö,Lund University Research Groups(Swepub:lu)med-js4 (author)
  • Miftakhova, ReginaUmeå University,Lund University,Lunds universitet,Experimentell cancerforskning, Malmö,Forskargrupper vid Lunds universitet,Experimental Cancer Research, Malmö,Lund University Research Groups,Kazan Federal University(Swepub:lu)med-rem (author)
  • Simoulis, AthanasiosDepartment of Clinical Pathology and Cytology, Skåne University Hospital, Malmö, Sweden (author)
  • Robinson, BrianDepartment of Pathology, Weill Cornell Medical College, New York, NY, USA (author)
  • Gjörloff Wingren, AnetteMalmö University,Malmö högskola,Institutionen för biomedicinsk vetenskap (BMV),Biofilms Research Center for Biointerfaces(Swepub:lu)mikr-agj (author)
  • Mongan, Nigel PFaculty of Medicine and Health Sciences, School of Veterinary Medicine and Sciences, University of Nottingham, Nottingham, United Kingdom(Swepub:lu)med-ngm (author)
  • Heery, DavidSchool of Pharmacy, University of Nottingham, Nottingham, United Kingdom (author)
  • Johnsson, HeatherDepartment of Bio-Diagnosis, Beijing Institute of Basic Medical Sciences, Beijing, China (author)
  • Abrahamsson, Per-AndersLund University,Lunds universitet,Urologi, Malmö (Abrahamsson),Forskargrupper vid Lunds universitet,Urological research, Malmö,Lund University Research Groups(Swepub:lu)uro-paa (author)
  • Dizeyi, NishtmanLund University,Lunds universitet,Urologi, Malmö (Abrahamsson),Forskargrupper vid Lunds universitet,Urological research, Malmö,Lund University Research Groups(Swepub:lu)kir-dni (author)
  • Luo, JonDepartment of Urology, the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA (author)
  • Persson, Jenny LUmeå University,Lund University,Lunds universitet,Experimentell cancerforskning, Malmö,Forskargrupper vid Lunds universitet,Experimental Cancer Research, Malmö,Lund University Research Groups(Swepub:lu)medk-jpe (author)
  • Experimentell cancerforskning, MalmöForskargrupper vid Lunds universitet (creator_code:org_t)

Related titles

  • In:Oncotarget: Impact Journals7:39, s. 63065-630811949-2553

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