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Targeted suppressio...
Targeted suppression of AR-V7 using PIP5K1α inhibitor overcomes enzalutamide resistance in prostate cancer cells
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- Sarwar, Martuza (author)
- Lund University,Lunds universitet,Experimentell cancerforskning, Malmö,Forskargrupper vid Lunds universitet,Experimental Cancer Research, Malmö,Lund University Research Groups
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- Semenas, Julius (author)
- Umeå University,Lund University,Lunds universitet,Experimentell cancerforskning, Malmö,Forskargrupper vid Lunds universitet,Experimental Cancer Research, Malmö,Lund University Research Groups
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- Miftakhova, Regina (author)
- Umeå University,Lund University,Lunds universitet,Experimentell cancerforskning, Malmö,Forskargrupper vid Lunds universitet,Experimental Cancer Research, Malmö,Lund University Research Groups,Kazan Federal University
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- Simoulis, Athanasios (author)
- Department of Clinical Pathology and Cytology, Skåne University Hospital, Malmö, Sweden
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- Robinson, Brian (author)
- Department of Pathology, Weill Cornell Medical College, New York, NY, USA
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- Gjörloff Wingren, Anette (author)
- Malmö University,Malmö högskola,Institutionen för biomedicinsk vetenskap (BMV),Biofilms Research Center for Biointerfaces
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- Mongan, Nigel P (author)
- Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Sciences, University of Nottingham, Nottingham, United Kingdom
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- Heery, David (author)
- School of Pharmacy, University of Nottingham, Nottingham, United Kingdom
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- Johnsson, Heather (author)
- Department of Bio-Diagnosis, Beijing Institute of Basic Medical Sciences, Beijing, China
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- Abrahamsson, Per-Anders (author)
- Lund University,Lunds universitet,Urologi, Malmö (Abrahamsson),Forskargrupper vid Lunds universitet,Urological research, Malmö,Lund University Research Groups
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- Dizeyi, Nishtman (author)
- Lund University,Lunds universitet,Urologi, Malmö (Abrahamsson),Forskargrupper vid Lunds universitet,Urological research, Malmö,Lund University Research Groups
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- Luo, Jon (author)
- Department of Urology, the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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- Persson, Jenny L (author)
- Umeå University,Lund University,Lunds universitet,Experimentell cancerforskning, Malmö,Forskargrupper vid Lunds universitet,Experimental Cancer Research, Malmö,Lund University Research Groups
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(creator_code:org_t)
- 2016-08-31
- 2016
- English.
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In: Oncotarget. - : Impact Journals. - 1949-2553. ; 7:39, s. 63065-63081
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Abstract
Subject headings
Close
- 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
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- prostate cancer metastasis
- enzalutamide resistance
- lipid kinase inhibitor
- AR-V7
- PIP5K1a
- Prostate cancer metastasis
- enzalutamide resistance
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Sarwar, Martuza
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Semenas, Julius
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Miftakhova, Regi ...
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Simoulis, Athana ...
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Robinson, Brian
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Gjörloff Wingren ...
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Mongan, Nigel P
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Heery, David
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Johnsson, Heathe ...
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Abrahamsson, Per ...
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Dizeyi, Nishtman
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Luo, Jon
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Persson, Jenny L
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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Oncotarget
- By the university
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Malmö University
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Lund University