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Targeted suppression of AR-V7 using PIP5K1? inhibitor overcomes enzalutamide resistance in prostate cancer cells
- Publication Year :
- 2016
- Publisher :
- Impact Journals, 2016.
-
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 PIP5K1? as a drug target in PCa. In this study, we show that AR-V7 expression positively correlates with PIP5K1? in tumor specimens from PCa patients. Overexpression of AR-V7 increases PIP5K1?, promotes rapid growth of PCa in xenograft mice, whereas inhibition of PIP5K1? by its inhibitor ISA-2011B suppresses the growth and invasiveness of xenograft tumors overexpressing AR-V7. PIP5K1? 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? 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?, leading to suppression of invasive growth of AR-V7-high tumors in xenograft mice. Our study suggests that combination of enzalutamide and PIP5K1? may have a significant impact on refining therapeutic strategies to circumvent resistance to antiandrogen therapies.
Details
- Language :
- English
- ISSN :
- 19492553
- Database :
- OpenAIRE
- Accession number :
- edsair.core.ac.uk....a8fac6a7254fb969aff3a1f1ed424d5e