Asim, M., Massie, C. E., Orafidiya, F., Pertega-Gomes, N., Warren, A. Y., Esmaeili, M., Selth, L. A., Zecchini, H. I., Luko, K., Qureshi, A., Baridi, A., Menon, S., Madhu, B., Escriu, C., Lyons, S., Vowler, S. L., Zecchini, V. R., Shaw, G., Hessenkemper, W., Russell, R., Mohammed, H., Stefanos, N., Lynch, A. G., Grigorenko, E., D'Santos, C., Taylor, C., Lamb, A., Sriranjan, R., Yang, J., Stark, R., Dehm, S. M., Rennie, P. S., Carroll, J. S., Griffiths, J. R., Tavare, S., Mills, I. G., McEwan, I. J., Baniahmad, A., Tilley, W. D., Neal, D. E. (May 2016) Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target. J Natl Cancer Inst, 108 (5). ISSN 1460-2105 (Electronic)0027-8874 (Linking)
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 chi(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.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Aged Animals Antineoplastic Agents/*pharmacology Biomarkers, Tumor/*metabolism Choline Kinase/antagonists & inhibitors/genetics/*metabolism Enzyme Inhibitors/pharmacology Gene Expression Regulation, Neoplastic Humans Kaplan-Meier Estimate Male Mice Mice, Inbred NOD Mice, SCID Middle Aged *Molecular Chaperones Molecular Targeted Therapy/*methods Neoplasm Grading Neoplasm Staging Proportional Hazards Models *Prostatectomy/methods Prostatic Neoplasms/*drug therapy/*enzymology/pathology/surgery Receptors, Androgen/*metabolism Sequence Analysis, DNA *Signal Transduction Xenograft Model Antitumor Assays |
| Subjects: | diseases & disorders > cancer > cancer types > prostate cancer |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program > Cancer Genetics CSHL labs > Lyons lab CSHL Cancer Center Program > Cellular Communication in Cancer Program |
| Depositing User: | Matt Covey |
| Date: | May 2016 |
| Date Deposited: | 12 May 2017 20:18 |
| Last Modified: | 26 Oct 2020 15:56 |
| PMCID: | PMC4849803 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/34710 |
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