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

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

Research output: Contribution to journalArticle

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 (PIP5Ka), is a lipid kinase that links to CDK1 and AR pathways. The discovery of PIP5Ka 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.

Original languageEnglish (US)
Pages (from-to)63065-63081
Number of pages17
JournalOncotarget
Volume7
Issue number39
DOIs
StatePublished - 2016

Fingerprint

Prostatic Neoplasms
Heterografts
Growth
Androgen Antagonists
Neoplasms
Proteins
Phosphotransferases
Therapeutics
MDV 3100
Ligands
Lipids
Pharmaceutical Preparations
1-phosphatidylinositol-4-phosphate 5-kinase
ISA-2011B

Keywords

  • AR-V7
  • Enzalutamide resistance
  • Lipid kinase inhibitor
  • PIP5K1α
  • Prostate cancer metastasis

ASJC Scopus subject areas

  • Oncology

Cite this

Sarwar, M., Semenas, J., Miftakhova, R., Simoulis, A., Robinson, B., Wingren, A. G., ... Persson, J. L. (2016). Targeted suppression of AR-V7 using PIP5K1α inhibitor overcomes enzalutamide resistance in prostate cancer cells. Oncotarget, 7(39), 63065-63081. https://doi.org/10.18632/oncotarget.11757

Targeted suppression of AR-V7 using PIP5K1α inhibitor overcomes enzalutamide resistance in prostate cancer cells. / Sarwar, Martuza; Semenas, Julius; Miftakhova, Regina; Simoulis, Athanasios; Robinson, Brian; Wingren, Anette Gjörloff; Mongan, Nigel P.; Heery, David M.; Johnsson, Heather; Abrahamsson, Per Anders; Dizeyi, Nishtman; Luo, Jun; Persson, Jenny L.

In: Oncotarget, Vol. 7, No. 39, 2016, p. 63065-63081.

Research output: Contribution to journalArticle

Sarwar, M, Semenas, J, Miftakhova, R, Simoulis, A, Robinson, B, Wingren, AG, Mongan, NP, Heery, DM, Johnsson, H, Abrahamsson, PA, Dizeyi, N, Luo, J & Persson, JL 2016, 'Targeted suppression of AR-V7 using PIP5K1α inhibitor overcomes enzalutamide resistance in prostate cancer cells', Oncotarget, vol. 7, no. 39, pp. 63065-63081. https://doi.org/10.18632/oncotarget.11757
Sarwar, Martuza ; Semenas, Julius ; Miftakhova, Regina ; Simoulis, Athanasios ; Robinson, Brian ; Wingren, Anette Gjörloff ; Mongan, Nigel P. ; Heery, David M. ; Johnsson, Heather ; Abrahamsson, Per Anders ; Dizeyi, Nishtman ; Luo, Jun ; Persson, Jenny L. / Targeted suppression of AR-V7 using PIP5K1α inhibitor overcomes enzalutamide resistance in prostate cancer cells. In: Oncotarget. 2016 ; Vol. 7, No. 39. pp. 63065-63081.
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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 (PIP5Ka), is a lipid kinase that links to CDK1 and AR pathways. The discovery of PIP5Ka 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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