Journal Article

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

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

2011

Overview

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. Using a combination of genomic and metabolomic profiling strategies, the CAMKK2 kinase is identified as a critical downstream target of the androgen receptor. CAMKK2 regulates anabolic flux, and represents an attractive therapeutic target for prostate cancer treatments.

• Publisher: John Wiley & Sons, Ltd,Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: androgen receptor / Androgens / Animals / Base Sequence / Binding Sites - genetics / Biosynthesis / Biosynthetic Pathways - genetics / Calcium / Carcinoma - genetics / Carcinoma - metabolism / Carcinoma - pathology / Cell Line, Tumor / Cell Proliferation / Cellular biology / Chromatin / Cluster Analysis / EMBO24 / EMBO43 / Gene Expression Regulation, Neoplastic / Humans / Male / Metabolism / Metabolism - genetics / Metabolism - physiology / Mice / Models, Biological / Molecular biology / Prostate cancer / Prostatic Neoplasms - genetics / Prostatic Neoplasms - metabolism / Prostatic Neoplasms - pathology / Receptors, Androgen - genetics / Receptors, Androgen - metabolism / Receptors, Androgen - physiology / Response Elements - genetics / transcription / Transplantation, Heterologous / Tumors