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

Sarwar, Martuza LU ; Semenas, Julius LU ; Miftakhova, Regina LU ; Simoulis, Athanasios; Robinson, Brian; Wingren, Anette Gjörloff LU ; Mongan, Nigel P LU ; Heery, David M; Johnsson, Heather and Abrahamsson, Per-Anders LU , et al. (2016) In Oncotarget 7(39). p.63065-63081
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... (More)

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.

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published
subject
keywords
Prostate cancer metastasis, enzalutamide resistance
in
Oncotarget
volume
7
issue
39
pages
63065 - 63081
publisher
Impact Journals, LLC
ISSN
1949-2553
DOI
10.18632/oncotarget.11757
language
English
LU publication?
yes
id
c6f4b8b1-8a89-4df0-9e06-368b57eb49be
date added to LUP
2016-09-14 15:27:22
date last changed
2016-12-05 11:16:42
@misc{c6f4b8b1-8a89-4df0-9e06-368b57eb49be,
  abstract     = {<p>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.</p>},
  author       = {Sarwar, Martuza and Semenas, Julius and Miftakhova, Regina and Simoulis, Athanasios and Robinson, Brian and Wingren, Anette Gjörloff and Mongan, Nigel P and Heery, David M and Johnsson, Heather and Abrahamsson, Per-Anders and Dizeyi, Nishtman and Luo, Jun and Persson, Jenny L},
  issn         = {1949-2553},
  keyword      = {Prostate cancer metastasis,enzalutamide resistance},
  language     = {eng},
  month        = {08},
  number       = {39},
  pages        = {63065--63081},
  publisher    = {ARRAY(0xb879dc8)},
  series       = {Oncotarget},
  title        = {Targeted suppression of AR-V7 using PIP5K1α inhibitor overcomes enzalutamide resistance in prostate cancer cells},
  url          = {http://dx.doi.org/10.18632/oncotarget.11757},
  volume       = {7},
  year         = {2016},
}