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 Russell; Hisham 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

doi:10.1093/jnci/djv371

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

Medical Sciences

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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 language	English
Article number	djv371
Number of pages	13
Journal	Journal of the National Cancer Institute
Volume	108
Issue number	5
Early online date	11 Dec 2015
DOIs	https://doi.org/10.1093/jnci/djv371
Publication status	Published - May 2016

Bibliographical note

Funding
This work was supported by a Cancer Research UK program
grant (to DEN) and also by the US Department of Defense
(Prostate Cancer Research Program Transformative Impact
Award, grant ID W81XWH-13-2-0093 to WDT and SMD), PCFA/
Cancer Australia/Movember (grant IDs 1012337 and 1043482
to WDT and LAS), Cancer Australia (grant ID 1043497 to WDT
and JC), and The Ray and Shirl Norman Cancer Research Trust
(to WDT and LAS). The Dame Roma Mitchell Cancer Research
Laboratories were supported by an establishment grant from
the Prostate Cancer Foundation Australia (ID 2011/0452). FO was
supported by a PhD project grant from Prostate Cancer UK (S10-
10). LAS is supported by a Young Investigator Award from the
Prostate Cancer Foundation (the Foundation 14 award).

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Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target
© 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.
Final published version, 1.88 MBLicence: CC BY

Iain McEwan
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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), Article djv371. https://doi.org/10.1093/jnci/djv371

Asim, M, Massie, CE, Orafidiya, F, Pertega-Gomes, N, Warren, AY, Esmaeili, M, Selth, LA, Zecchini, HI, Luko, K, Qureshi, A, Baridi, A, Menon, S, Madhu, B, Escriu, C, Lyons, S, Vowler, SL, Zecchini, VR, Shaw, G, Hessenkemper, W, Russell, R, Mohammed, H, Stefanos, N, Lynch, AG, Grigorenko, E, D'Santos, C, Taylor, C, Lamb, A, Sriranjan, R, Yang, J, Stark, R, Dehm, SM, Rennie, PS, Carroll, JS, Griffiths, JR, Tavare, S, Mills, IG, McEwan, IJ, Baniahmad, A, Tilley, WD & Neal, DE 2016, 'Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target', Journal of the National Cancer Institute, vol. 108, no. 5, djv371. https://doi.org/10.1093/jnci/djv371

@article{ace6243e9dfc4ff79d8f5689334c5094,

title = "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.",

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

note = "Funding This work was supported by a Cancer Research UK program grant (to DEN) and also by the US Department of Defense (Prostate Cancer Research Program Transformative Impact Award, grant ID W81XWH-13-2-0093 to WDT and SMD), PCFA/ Cancer Australia/Movember (grant IDs 1012337 and 1043482 to WDT and LAS), Cancer Australia (grant ID 1043497 to WDT and JC), and The Ray and Shirl Norman Cancer Research Trust (to WDT and LAS). The Dame Roma Mitchell Cancer Research Laboratories were supported by an establishment grant from the Prostate Cancer Foundation Australia (ID 2011/0452). FO was supported by a PhD project grant from Prostate Cancer UK (S10- 10). LAS is supported by a Young Investigator Award from the Prostate Cancer Foundation (the Foundation 14 award).",

year = "2016",

month = may,

doi = "10.1093/jnci/djv371",

language = "English",

volume = "108",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "5",

}

TY - JOUR

T1 - Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target

AU - Asim, Mohammad

AU - Massie, Charles E.

AU - Orafidiya, Folake

AU - Pertega-Gomes, Nelma

AU - Warren, Anne Y.

AU - Esmaeili, Mohsen

AU - Selth, Luke A.

AU - Zecchini, Heather I.

AU - Luko, Katarina

AU - Qureshi, Arham

AU - Baridi, Ajoeb

AU - Menon, Suraj

AU - Madhu, Basetti

AU - Escriu, Carlos

AU - Lyons, Scott

AU - Vowler, Sarah L.

AU - Zecchini, Vincent R.

AU - Shaw, Greg

AU - Hessenkemper, Wiebke

AU - Russell, Roslin

AU - Mohammed, Hisham

AU - Stefanos, Niki

AU - Lynch, Andy G.

AU - Grigorenko, Elena

AU - D'Santos, Clive

AU - Taylor, Chris

AU - Lamb, Alistair

AU - Sriranjan, Rouchelle

AU - Yang, Jiali

AU - Stark, Rory

AU - Dehm, Scott M.

AU - Rennie, Paul S.

AU - Carroll, Jason S.

AU - Griffiths, John R.

AU - Tavare, Simon

AU - Mills, Ian G.

AU - McEwan, Iain J.

AU - Baniahmad, Aria

AU - Tilley, Wayne D.

AU - Neal, David E.

N1 - Funding This work was supported by a Cancer Research UK program grant (to DEN) and also by the US Department of Defense (Prostate Cancer Research Program Transformative Impact Award, grant ID W81XWH-13-2-0093 to WDT and SMD), PCFA/ Cancer Australia/Movember (grant IDs 1012337 and 1043482 to WDT and LAS), Cancer Australia (grant ID 1043497 to WDT and JC), and The Ray and Shirl Norman Cancer Research Trust (to WDT and LAS). The Dame Roma Mitchell Cancer Research Laboratories were supported by an establishment grant from the Prostate Cancer Foundation Australia (ID 2011/0452). FO was supported by a PhD project grant from Prostate Cancer UK (S10- 10). LAS is supported by a Young Investigator Award from the Prostate Cancer Foundation (the Foundation 14 award).

PY - 2016/5

Y1 - 2016/5

N2 - 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.

AB - 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.

U2 - 10.1093/jnci/djv371

DO - 10.1093/jnci/djv371

M3 - Article

C2 - 26657335

SN - 0027-8874

VL - 108

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 5

M1 - djv371

ER -

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

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