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

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.

• Authors: Mohammad Asim, Charles E Massie, Folake Orafidiya, Nelma Pértega-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 Russell, Hisham Mohammed, Niki Stefanos, Andy G Lynch, Elena Grigorenko, Clive D'Santos, Chris Taylor, Alastair Lamb, Rouchelle Sriranjan, Jiali Yang, Rory Stark, Scott M Dehm, Paul S Rennie, Jason S Carroll, John R Griffiths, Simon Tavaré, Ian G Mills, Iain J McEwan, Aria Baniahmad, Wayne D Tilley, David E Neal
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 108 Issue 5 (May 2016) ISSN: 1460-2105 [Electronic] United States
• PMID: 26657335 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © The Author 2015. Published by Oxford University Press.

Chemical References

• AR protein, human
• Antineoplastic Agents
• Biomarkers, Tumor
• Enzyme Inhibitors
• Molecular Chaperones
• Receptors, Androgen
• CHKA protein, human
• Choline Kinase

Topics

• 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