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.
authors: CRUK Cambridge Research Institute, Cambridge, UK.
authors: Charles E
authors: CE
authors: Massie
authors: Andy
authors: A
authors: Lynch
authors: Antonio
authors: A
authors: Ramos-Montoya
authors: Joan
authors: J
authors: Boren
authors: Rory
authors: R
authors: Stark
authors: Ladan
authors: L
authors: Fazli
authors: Anne
authors: A
authors: Warren
authors: Helen
authors: H
authors: Scott
authors: Basetti
authors: B
authors: Madhu
authors: Naomi
authors: N
authors: Sharma
authors: Helene
authors: H
authors: Bon
authors: Vinny
authors: V
authors: Zecchini
authors: Donna-Michelle
authors: DM
authors: Smith
authors: Gina M
authors: GM
authors: Denicola
authors: Nik
authors: N
authors: Mathews
authors: Michelle
authors: M
authors: Osborne
authors: James
authors: J
authors: Hadfield
authors: Stewart
authors: S
authors: Macarthur
authors: Boris
authors: B
authors: Adryan
authors: Scott K
authors: SK
authors: Lyons
authors: Kevin M
authors: KM
authors: Brindle
authors: John
authors: J
authors: Griffiths
authors: Martin E
authors: ME
authors: Gleave
authors: Paul S
authors: PS
authors: Rennie
authors: David E
authors: DE
authors: Neal
authors: Ian G
authors: IG
authors: Mills
references: PLoS One. 2009 Aug 11;4(8):e6589
references: 19668381
references: Clin Cancer Res. 2009 Jan 1;15(1):39-47
references: 19118031
references: Mol Cell. 2007 Aug 3;27(3):380-92
references: 17679089
references: J Clin Oncol. 2009 Aug 10;27(23):3742-8
references: 19470933
references: J Biol Chem. 1998 Aug 7;273(32):20213-22
references: 9685369
references: Mol Endocrinol. 1992 Dec;6(12):2229-35
references: 1491700
references: Cell. 2009 Jul 23;138(2):245-56
references: 19632176
references: Cancer Res. 2008 Sep 15;68(18):7475-83
references: 18794135
references: Oncogene. 2007 Jun 28;26(30):4453-63
references: 17297473
references: PLoS One. 2008;3(11):e3645
references: 18997859
references: Biochem Biophys Res Commun. 2006 Jan 6;339(1):99-106
references: 16289377
references: J Steroid Biochem Mol Biol. 2005 Aug;96(3-4):251-8
references: 15982869
references: J Biol Chem. 2003 Aug 1;278(31):28395-402
references: 12750369
references: Cancer Res. 2009 Aug 15;69(16):6522-30
references: 19654297
references: Science. 2008 Oct 17;322(5900):434-8
references: 18787134
references: Nature. 2008 Mar 13;452(7184):230-3
references: 18337823
references: Cancer Res. 2011 Jan 15;71(2):528-37
references: 21098087
references: Mol Cell. 2008 Apr 25;30(2):214-26
references: 18439900
references: Mol Cancer Ther. 2009 Apr;8(4):733-41
references: 19372545
references: Nat Cell Biol. 2007 Feb;9(2):218-24
references: 17237771
references: Prostate. 2007 Sep 15;67(13):1371-83
references: 17624924
references: Cancer Res. 2006 Aug 1;66(15):7783-92
references: 16885382
references: Oncogene. 2007 Apr 5;26(16):2386-94
references: 17016436
references: Nat Genet. 1995 Apr;9(4):401-6
references: 7795646
references: Nucleic Acids Res. 2005 Mar 10;33(5):1445-53
references: 15760844
references: Science. 2008 Dec 19;322(5909):1845-8
references: 19056941
references: Nat Genet. 2006 Nov;38(11):1289-97
references: 17013392
references: Cancer Res. 2002 May 15;62(10):2942-50
references: 12019176
references: Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21660-5
references: 19995986
references: Cell. 2006 Apr 21;125(2):315-26
references: 16630819
references: Science. 2009 May 22;324(5930):1029-33
references: 19460998
references: Mol Cancer. 2007 Jun 06;6:38
references: 17553164
references: Oncogene. 2003 Mar 6;22(9):1381-9
references: 12618764
references: Mol Endocrinol. 2001 Oct;15(10):1817-28
references: 11579213
references: J Biol Chem. 2004 Jul 16;279(29):30880-7
references: 15133039
references: PLoS One. 2008;3(11):e3713
references: 19002256
references: Cancer Res. 2008 Feb 15;68(4):1128-35
references: 18281488
references: Genes Dev. 2007 Aug 15;21(16):2005-17
references: 17699749
references: Nat Genet. 2003 Jul;34(3):267-73
references: 12808457
references: Endocrinology. 2004 Aug;145(8):3913-24
references: 15131019
references: J Biol Chem. 1997 Nov 14;272(46):28875-81
references: 9360955
references: Cell. 2007 May 18;129(4):823-37
references: 17512414
references: Curr Protoc Bioinformatics. 2007 Sep;Chapter 10:Unit 10.5
references: 18428782
references: Cancer Res. 2009 May 15;69(10):4434-42
references: 19366804
references: Genome Biol. 2008;9(9):R137
references: 18798982
references: Biochem Biophys Res Commun. 2004 Dec 24;325(4):1312-7
references: 15555570
references: J Natl Cancer Inst. 2009 Apr 1;101(7):519-32
references: 19318631
references: Mol Cancer. 2006 Nov 24;5:64
references: 17123452
references: Bioinformatics. 2007 Aug 15;23(16):2183-4
references: 17586828
references: Science. 2010 Sep 17;329(5998):1492-9
references: 20847263
references: Cancer Cell. 2005 Nov;8(5):393-406
references: 16286247
references: Genome Res. 2008 Nov;18(11):1851-8
references: 18714091
references: Bioinformatics. 2008 Dec 15;24(24):2921-2
references: 18953044
references: Biochem Biophys Res Commun. 1990 Dec 14;173(2):534-40
references: 2260966
references: Curr Biol. 2000 Oct 19;10(20):1247-55
references: 11069105
references: Mol Cancer. 2007 Jun 06;6:39
references: 17553165
references: Anal Biochem. 2008 Jan 15;372(2):204-12
references: 17963684
references: J Biol Chem. 1974 Dec 25;249(24):7824-31
references: 4279251
references: Genome Res. 2007 Jun;17(6):960-4
references: 17568012
references: Mol Cell Endocrinol. 2011 Jan 1;331(1):57-65
references: 20728506
references: Nat Med. 1999 Mar;5(3):280-5
references: 10086382
references: Science. 2007 Jun 8;316(5830):1497-502
references: 17540862
references: Cancer Cell. 2010 May 18;17(5):443-54
references: 20478527
references: JAMA. 2002 Jun 19;287(23):3080-1; author reply 3081
references: 12069667
references: J Biol Chem. 2002 May 3;277(18):15813-8
references: 11867640
references: Neoplasia. 2004 Jan-Feb;6(1):1-6
references: 15068665
references: Proc Int Conf Intell Syst Mol Biol. 1995;3:21-9
references: 7584439
references: Am J Surg Pathol. 2001 Nov;25(11):1397-404
references: 11684956
references: EMBO Rep. 2007 Sep;8(9):871-8
references: 17721441
references: Cell Metab. 2008 May;7(5):377-88
references: 18460329
references: Science. 2009 May 8;324(5928):787-90
references: 19359544
references: Oncogene. 2009 May 7;28(18):1993-2002
references: 19347029