Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/119733
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Type: Journal article
Title: Choline kinase alpha as an androgen receptor chaperone and prostate cancer therapeutic target
Author: Asim, M.
Massie, C.
Orafidiya, F.
Pértega-Gomes, N.
Warren, A.
Esmaeili, M.
Selth, L.
Zecchini, H.
Luko, K.
Qureshi, A.
Baridi, A.
Menon, S.
Madhu, B.
Escriu, C.
Lyons, S.
Vowler, S.
Zecchini, V.
Shaw, G.
Hessenkemper, W.
Russell, R.
et al.
Citation: Journal of the National Cancer Institute, 2016; 108(5):djv371-1-djv371-13
Publisher: Oxford University Press
Issue Date: 2016
ISSN: 0027-8874
1460-2105
Statement of
Responsibility: 
Mohammad Asim ... Luke A. Selth ... Wayne D. Tilley et al.
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.
Keywords: Animals
Mice, Inbred NOD
Humans
Mice
Mice, SCID
Prostatic Neoplasms
Choline Kinase
Molecular Chaperones
Receptors, Androgen
Antineoplastic Agents
Enzyme Inhibitors
Neoplasm Staging
Prostatectomy
Proportional Hazards Models
Xenograft Model Antitumor Assays
Sequence Analysis, DNA
Signal Transduction
Gene Expression Regulation, Neoplastic
Aged
Middle Aged
Male
Kaplan-Meier Estimate
Molecular Targeted Therapy
Neoplasm Grading
Biomarkers, Tumor
Rights: © The Author 2015. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
DOI: 10.1093/jnci/djv371
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