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

Research output: Contribution to journalArticle

319 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 languageEnglish
Pages (from-to)2719-33
Number of pages15
JournalThe EMBO Journal
Volume30
Issue number13
DOIs
Publication statusPublished - 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

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  • Cite this

    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