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Targeted suppressio...
Targeted suppression of AR-V7 using PIP5K1 alpha inhibitor overcomes enzalutamide resistance in prostate cancer cells
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Sarwar, Martuza (author)
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- Semenas, Julius (author)
- Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden
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- Miftakhova, Regina (author)
- Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden; Department of Genetics, Kazan Federal University, Kazan, Russia
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Simoulis, Athanasios (author)
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Robinson, Brian (author)
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Wingren, Anette Gjorloff (author)
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Mongan, Nigel P. (author)
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Heery, David M. (author)
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Johnsson, Heather (author)
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Abrahamsson, Per-Anders (author)
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Dizeyi, Nishtman (author)
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Luo, Jun (author)
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- Persson, Jenny L. (author)
- Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden
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(creator_code:org_t)
- 2016-08-31
- 2016
- English.
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In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:39, s. 63065-63081
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Abstract
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- 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 (PIP5K alpha), is a lipid kinase that links to CDK1 and AR pathways. The discovery of PIP5K alpha inhibitor highlight the potential of PIP5K1 alpha as a drug target in PCa. In this study, we show that AR-V7 expression positively correlates with PIP5K1 alpha in tumor specimens from PCa patients. Overexpression of AR-V7 increases PIP5K1 alpha, promotes rapid growth of PCa in xenograft mice, whereas inhibition of PIP5K1 alpha by its inhibitor ISA-2011B suppresses the growth and invasiveness of xenograft tumors overexpressing AR-V7. PIP5K1 alpha 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, PIP5K1 alpha 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 PIP5K1 alpha, leading to suppression of invasive growth of AR-V7-high tumors in xenograft mice. Our study suggests that combination of enzalutamide and PIP5K1 alpha 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
- PIP5K1α
Publication and Content Type
- ref (subject category)
- art (subject category)
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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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Wingren, Anette ...
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Mongan, Nigel P.
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Heery, David M.
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Johnsson, Heathe ...
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Abrahamsson, Per ...
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Dizeyi, Nishtman
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Luo, Jun
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Persson, Jenny L ...
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- MEDICAL AND HEALTH SCIENCES
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Oncotarget
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Umeå University