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

In English

Författare

  • Martuza Sarwar
  • Julius Semenas
  • Regina Miftakhova
  • Athanasios Simoulis
  • Brian Robinson
  • Anette Gjörloff Wingren
  • Nigel P Mongan
  • David M Heery
  • Heather Johnsson
  • Per-Anders Abrahamsson
  • Nishtman Dizeyi
  • Jun Luo
  • Jenny L Persson
Visa allt

Summary, in English

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.

Avdelning/ar

Publiceringsår

2016-08-31

Språk

Engelska

Sidor

63065-63081

Publikation/Tidskrift/Serie

Oncotarget

Volym

7

Issue

39

Dokumenttyp

Artikel i tidskrift

Förlag

Impact Journals

Ämne

  • Cancer and Oncology

Nyckelord

  • Prostate cancer metastasis
  • enzalutamide resistance

Status

Published

Forskningsgrupp

  • Experimental Cancer Research, Malmö
  • Urological research, Malmö

ISBN/ISSN/Övrigt

  • ISSN: 1949-2553