The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis

Charles E Massie; Andy Lynch; Antonio Ramos-Montoya; Joan Boren; Rory Stark; Ladan Fazli; Anne Warren; Helen Scott; Basetti Madhu; Naomi Sharma; Helene Bon; Vinny Zecchini; Donna-Michelle Smith; Gina M Denicola; Nik Mathews; Michelle Osborne; James Hadfield; Stewart Macarthur; Boris Adryan; Scott K Lyons; Kevin M Brindle; John Griffiths; Martin E Gleave; Paul S Rennie; David E Neal; Ian G Mills

doi:10.1038/emboj.2011.158

The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis

Charles E Massie, Andy Lynch, Antonio Ramos-Montoya, Joan Boren, Rory Stark, Ladan Fazli, Anne Warren, Helen Scott, Basetti Madhu, Naomi Sharma, Helene Bon, Vinny Zecchini, Donna-Michelle Smith, Gina M Denicola, Nik Mathews, Michelle Osborne, James Hadfield, Stewart Macarthur, Boris Adryan, Scott K LyonsKevin M Brindle, John Griffiths, Martin E Gleave, Paul S Rennie, David E Neal, Ian G Mills

School of Medicine, Dentistry and Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

494 Citations (Scopus)

Abstract

The androgen receptor (AR) is a key regulator of prostate growth and the principal drug target for the treatment of prostate cancer. Previous studies have mapped AR targets and identified some candidates which may contribute to cancer progression, but did not characterize AR biology in an integrated manner. In this study, we took an interdisciplinary approach, integrating detailed genomic studies with metabolomic profiling and identify an anabolic transcriptional network involving AR as the core regulator. Restricting flux through anabolic pathways is an attractive approach to deprive tumours of the building blocks needed to sustain tumour growth. Therefore, we searched for targets of the AR that may contribute to these anabolic processes and could be amenable to therapeutic intervention by virtue of differential expression in prostate tumours. This highlighted calcium/calmodulin-dependent protein kinase kinase 2, which we show is overexpressed in prostate cancer and regulates cancer cell growth via its unexpected role as a hormone-dependent modulator of anabolic metabolism. In conclusion, it is possible to progress from transcriptional studies to a promising therapeutic target by taking an unbiased interdisciplinary approach.

Original language	English
Pages (from-to)	2719-33
Number of pages	15
Journal	The EMBO Journal
Volume	30
Issue number	13
DOIs	https://doi.org/10.1038/emboj.2011.158
Publication status	Published - 06 Jul 2011

Keywords

Animals
Base Sequence
Binding Sites
Biosynthetic Pathways
Carcinoma
Cell Line, Tumor
Cell Proliferation
Cluster Analysis
Gene Expression Regulation, Neoplastic
Humans
Male
Metabolism
Mice
Models, Biological
Prostatic Neoplasms
Receptors, Androgen
Response Elements
Transplantation, Heterologous

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/emboj.2011.158

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Massie, C. E., Lynch, A., Ramos-Montoya, A., Boren, J., Stark, R., Fazli, L., Warren, A., Scott, H., Madhu, B., Sharma, N., Bon, H., Zecchini, V., Smith, D.-M., Denicola, G. M., Mathews, N., Osborne, M., Hadfield, J., Macarthur, S., Adryan, B., ... Mills, I. G. (2011). The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis. The EMBO Journal, 30(13), 2719-33. https://doi.org/10.1038/emboj.2011.158

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title = "The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis",

abstract = "The androgen receptor (AR) is a key regulator of prostate growth and the principal drug target for the treatment of prostate cancer. Previous studies have mapped AR targets and identified some candidates which may contribute to cancer progression, but did not characterize AR biology in an integrated manner. In this study, we took an interdisciplinary approach, integrating detailed genomic studies with metabolomic profiling and identify an anabolic transcriptional network involving AR as the core regulator. Restricting flux through anabolic pathways is an attractive approach to deprive tumours of the building blocks needed to sustain tumour growth. Therefore, we searched for targets of the AR that may contribute to these anabolic processes and could be amenable to therapeutic intervention by virtue of differential expression in prostate tumours. This highlighted calcium/calmodulin-dependent protein kinase kinase 2, which we show is overexpressed in prostate cancer and regulates cancer cell growth via its unexpected role as a hormone-dependent modulator of anabolic metabolism. In conclusion, it is possible to progress from transcriptional studies to a promising therapeutic target by taking an unbiased interdisciplinary approach.",

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author = "Massie, {Charles E} and Andy Lynch and Antonio Ramos-Montoya and Joan Boren and Rory Stark and Ladan Fazli and Anne Warren and Helen Scott and Basetti Madhu and Naomi Sharma and Helene Bon and Vinny Zecchini and Donna-Michelle Smith and Denicola, {Gina M} and Nik Mathews and Michelle Osborne and James Hadfield and Stewart Macarthur and Boris Adryan and Lyons, {Scott K} and Brindle, {Kevin M} and John Griffiths and Gleave, {Martin E} and Rennie, {Paul S} and Neal, {David E} and Mills, {Ian G}",

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doi = "10.1038/emboj.2011.158",

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Massie, CE, Lynch, A, Ramos-Montoya, A, Boren, J, Stark, R, Fazli, L, Warren, A, Scott, H, Madhu, B, Sharma, N, Bon, H, Zecchini, V, Smith, D-M, Denicola, GM, Mathews, N, Osborne, M, Hadfield, J, Macarthur, S, Adryan, B, Lyons, SK, Brindle, KM, Griffiths, J, Gleave, ME, Rennie, PS, Neal, DE & Mills, IG 2011, 'The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis', The EMBO Journal, vol. 30, no. 13, pp. 2719-33. https://doi.org/10.1038/emboj.2011.158

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T1 - The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis

AU - Massie, Charles E

AU - Lynch, Andy

AU - Ramos-Montoya, Antonio

AU - Boren, Joan

AU - Stark, Rory

AU - Fazli, Ladan

AU - Warren, Anne

AU - Scott, Helen

AU - Madhu, Basetti

AU - Sharma, Naomi

AU - Bon, Helene

AU - Zecchini, Vinny

AU - Smith, Donna-Michelle

AU - Denicola, Gina M

AU - Mathews, Nik

AU - Osborne, Michelle

AU - Hadfield, James

AU - Macarthur, Stewart

AU - Adryan, Boris

AU - Lyons, Scott K

AU - Brindle, Kevin M

AU - Griffiths, John

AU - Gleave, Martin E

AU - Rennie, Paul S

AU - Neal, David E

AU - Mills, Ian G

PY - 2011/7/6

Y1 - 2011/7/6

N2 - The androgen receptor (AR) is a key regulator of prostate growth and the principal drug target for the treatment of prostate cancer. Previous studies have mapped AR targets and identified some candidates which may contribute to cancer progression, but did not characterize AR biology in an integrated manner. In this study, we took an interdisciplinary approach, integrating detailed genomic studies with metabolomic profiling and identify an anabolic transcriptional network involving AR as the core regulator. Restricting flux through anabolic pathways is an attractive approach to deprive tumours of the building blocks needed to sustain tumour growth. Therefore, we searched for targets of the AR that may contribute to these anabolic processes and could be amenable to therapeutic intervention by virtue of differential expression in prostate tumours. This highlighted calcium/calmodulin-dependent protein kinase kinase 2, which we show is overexpressed in prostate cancer and regulates cancer cell growth via its unexpected role as a hormone-dependent modulator of anabolic metabolism. In conclusion, it is possible to progress from transcriptional studies to a promising therapeutic target by taking an unbiased interdisciplinary approach.

AB - The androgen receptor (AR) is a key regulator of prostate growth and the principal drug target for the treatment of prostate cancer. Previous studies have mapped AR targets and identified some candidates which may contribute to cancer progression, but did not characterize AR biology in an integrated manner. In this study, we took an interdisciplinary approach, integrating detailed genomic studies with metabolomic profiling and identify an anabolic transcriptional network involving AR as the core regulator. Restricting flux through anabolic pathways is an attractive approach to deprive tumours of the building blocks needed to sustain tumour growth. Therefore, we searched for targets of the AR that may contribute to these anabolic processes and could be amenable to therapeutic intervention by virtue of differential expression in prostate tumours. This highlighted calcium/calmodulin-dependent protein kinase kinase 2, which we show is overexpressed in prostate cancer and regulates cancer cell growth via its unexpected role as a hormone-dependent modulator of anabolic metabolism. In conclusion, it is possible to progress from transcriptional studies to a promising therapeutic target by taking an unbiased interdisciplinary approach.

KW - Animals

KW - Base Sequence

KW - Binding Sites

KW - Biosynthetic Pathways

KW - Carcinoma

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Cluster Analysis

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Male

KW - Metabolism

KW - Mice

KW - Models, Biological

KW - Prostatic Neoplasms

KW - Receptors, Androgen

KW - Response Elements

KW - Transplantation, Heterologous

U2 - 10.1038/emboj.2011.158

DO - 10.1038/emboj.2011.158

M3 - Article

C2 - 21602788

SN - 0261-4189

VL - 30

SP - 2719

EP - 2733

JO - The EMBO Journal

JF - The EMBO Journal

IS - 13

ER -

The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis

Abstract

Keywords

UN SDGs

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