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

Mohammad Asim, Charles E. Massie, Folake Orafidiya, Nelma Pertega-Gomes, Anne Y. Warren, Mohsen Esmaeili, Luke A. Selth, Heather I. Zecchini, Katarina Luko, Arham Qureshi, Ajoeb Baridi, Suraj Menon, Basetti Madhu, Carlos Escriu, Scott Lyons, Sarah L. Vowler, Vincent R. Zecchini, Greg Shaw, Wiebke Hessenkemper, Roslin RussellHisham Mohammed, Niki Stefanos, Andy G. Lynch, Elena Grigorenko, Clive D'Santos, Chris Taylor, Alistair Lamb, Rouchelle Sriranjan, Jiali Yang, Rory Stark, Scott M. Dehm, Paul S. Rennie, Jason S. Carroll, John R. Griffiths, Simon Tavare, Ian G. Mills, Iain J. McEwan, Aria Baniahmad, Wayne D. Tilley, David E. Neal

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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.

Original languageEnglish
Article numberdjv371
Pages (from-to)1-13
Number of pages13
JournalJournal of the National Cancer Institute
Volume108
Issue number5
Early online date11 Dec 2015
DOIs
Publication statusPublished - May 2016

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    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., ... Neal, D. E. (2016). Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target. Journal of the National Cancer Institute, 108(5), 1-13. [djv371]. https://doi.org/10.1093/jnci/djv371