Choline kinase alpha as an androgen receptor chaperone and prostate cancer therapeutic target

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dc.contributor.authorAsim, M.
dc.contributor.authorMassie, C.
dc.contributor.authorOrafidiya, F.
dc.contributor.authorPértega-Gomes, N.
dc.contributor.authorWarren, A.
dc.contributor.authorEsmaeili, M.
dc.contributor.authorSelth, L.
dc.contributor.authorZecchini, H.
dc.contributor.authorLuko, K.
dc.contributor.authorQureshi, A.
dc.contributor.authorBaridi, A.
dc.contributor.authorMenon, S.
dc.contributor.authorMadhu, B.
dc.contributor.authorEscriu, C.
dc.contributor.authorLyons, S.
dc.contributor.authorVowler, S.
dc.contributor.authorZecchini, V.
dc.contributor.authorShaw, G.
dc.contributor.authorHessenkemper, W.
dc.contributor.authorRussell, R.
dc.contributor.authoret al.
dc.date.issued2016
dc.description.abstractBackground: 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.
dc.description.statementofresponsibilityMohammad Asim ... Luke A. Selth ... Wayne D. Tilley et al.
dc.identifier.citationJournal of the National Cancer Institute, 2016; 108(5):djv371-1-djv371-13
dc.identifier.doi10.1093/jnci/djv371
dc.identifier.issn0027-8874
dc.identifier.issn1460-2105
dc.identifier.orcidSelth, L. [0000-0002-4686-1418]
dc.identifier.orcidTilley, W. [0000-0003-1893-2626]
dc.identifier.urihttp://hdl.handle.net/2440/119733
dc.language.isoen
dc.publisherOxford University Press
dc.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.
dc.source.urihttps://doi.org/10.1093/jnci/djv371
dc.subjectAnimals
dc.subjectMice, Inbred NOD
dc.subjectHumans
dc.subjectMice
dc.subjectMice, SCID
dc.subjectProstatic Neoplasms
dc.subjectCholine Kinase
dc.subjectMolecular Chaperones
dc.subjectReceptors, Androgen
dc.subjectAntineoplastic Agents
dc.subjectEnzyme Inhibitors
dc.subjectNeoplasm Staging
dc.subjectProstatectomy
dc.subjectProportional Hazards Models
dc.subjectXenograft Model Antitumor Assays
dc.subjectSequence Analysis, DNA
dc.subjectSignal Transduction
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectMale
dc.subjectKaplan-Meier Estimate
dc.subjectMolecular Targeted Therapy
dc.subjectNeoplasm Grading
dc.subjectBiomarkers, Tumor
dc.titleCholine kinase alpha as an androgen receptor chaperone and prostate cancer therapeutic target
dc.typeJournal article
pubs.publication-statusPublished

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