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J Natl Cancer Inst. 2015 Dec 11;108(5). doi: 10.1093/jnci/djv371. Print 2016 May.

Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target.

Author information

1
Affiliations of authors:Cancer Research UK Cambridge Institute, University of Cambridge , Cambridge, UK (MA, CEM, NP, HIZ, AQ, AB, SM, BM, CE, SL, SW, VRZ, GS, RR, HM, AGL, CD, CT, AL, RS, JY, RS, JSC, JRG, ST, DEN); School of Medical Sciences, University of Aberdeen , Aberdeen, UK (FO, IJM); Department of Pathology, Addenbrooke's Hospital , Cambridge, UK (AYW, NS); Institute of Human Genetics, Jena University Hospital , Jena , Germany (ME, KL, WH, AB); Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, Faculty of Health Sciences, University of Adelaide , Australia (LAS, WDT); Freemasons Foundation Centre for Men's Health, School of Medicine, Faculty of Health Sciences, University of Adelaide , Australia (LAS, WDT); Diatherix , Huntsville, AL (EG); Masonic Cancer Center, University of Minnesota , Minneapolis, MN (SMD); The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia , Vancouver BC , Canada (PSR); Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital , Oslo , Norway (IGM); Department of Cancer Prevention, Institute of Cancer Research and Department of Urology, Oslo University Hospital , Oslo , Norway (IGM); Prostate Cancer UK/Movember Centre of Excellence, Queens University , Belfast , UK (IGM); Department of Oncology, Addenbrooke's Hospital , Cambridge, UK (MA, DEN).

Abstract

BACKGROUND:

The androgen receptor (AR) is a major drug target in prostate cancer (PCa). We profiled the AR-regulated kinome to identify clinically relevant and druggable effectors of AR signaling.

METHODS:

Using genome-wide approaches, we interrogated all AR regulated kinases. Among these, choline kinase alpha (CHKA) expression was evaluated in benign (n = 195), prostatic intraepithelial neoplasia (PIN) (n = 153) and prostate cancer (PCa) lesions (n = 359). We interrogated how CHKA regulates AR signaling using biochemical assays and investigated androgen regulation of CHKA expression in men with PCa, both untreated (n = 20) and treated with an androgen biosynthesis inhibitor degarelix (n = 27). We studied the effect of CHKA inhibition on the PCa transcriptome using RNA sequencing and tested the effect of CHKA inhibition on cell growth, clonogenic survival and invasion. Tumor xenografts (n = 6 per group) were generated in mice using genetically engineered prostate cancer cells with inducible CHKA knockdown. Data were analyzed with χ(2) tests, Cox regression analysis, and Kaplan-Meier methods. All statistical tests were two-sided.

RESULTS:

CHKA expression was shown to be androgen regulated in cell lines, xenografts, and human tissue (log fold change from 6.75 to 6.59, P = .002) and was positively associated with tumor stage. CHKA binds directly to the ligand-binding domain (LBD) of AR, enhancing its stability. As such, CHKA is the first kinase identified as an AR chaperone. Inhibition of CHKA repressed the AR transcriptional program including pathways enriched for regulation of protein folding, decreased AR protein levels, and inhibited the growth of PCa cell lines, human PCa explants, and tumor xenografts.

CONCLUSIONS:

CHKA can act as an AR chaperone, providing, to our knowledge, the first evidence for kinases as molecular chaperones, making CHKA both a marker of tumor progression and a potential therapeutic target for PCa.

PMID:
26657335
PMCID:
PMC4849803
DOI:
10.1093/jnci/djv371
[Indexed for MEDLINE]
Free PMC Article

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