title: Antiandrogens act as selective androgen receptor modulators at the proteome level in prostate cancer cells.
abstract: Current therapies for prostate cancer include antiandrogens, inhibitory ligands of the androgen receptor, which repress androgen-stimulated growth. These include the selective androgen receptor modulators cyproterone acetate and hydroxyflutamide and the complete antagonist bicalutamide. Their activity is partly dictated by the presence of androgen receptor mutations, which are commonly detected in patients who relapse while receiving antiandrogens, i.e. in castrate-resistant prostate cancer. To characterize the early proteomic response to these antiandrogens we used the LNCaP prostate cancer cell line, which harbors the androgen receptor mutation most commonly detected in castrate-resistant tumors (T877A), analyzing alterations in the proteome, and comparing these to the effect of these therapeutics upon androgen receptor activity and cell proliferation. The majority are regulated post-transcriptionally, possibly via nongenomic androgen receptor signaling. Differences detected between the exposure groups demonstrate subtle changes in the biological response to each specific ligand, suggesting a spectrum of agonistic and antagonistic effects dependent on the ligand used. Analysis of the crystal structures of the AR in the presence of cyproterone acetate, hydroxyflutamide, and DHT identified important differences in the orientation of key residues located in the AF-2 and BF-3 protein interaction surfaces. This further implies that although there is commonality in the growth responses between androgens and those antiandrogens that stimulate growth in the presence of a mutation, there may also be influential differences in the growth pathways stimulated by the different ligands. This therefore has implications for prostate cancer treatment because tumors may respond differently dependent upon which mutation is present and which ligand is activating growth, also for the design of selective androgen receptor modulators, which aim to elicit differential proteomic responses dependent upon cellular context.
authors.affiliation: From the ‡Androgen Signalling Laboratory, Imperial College London, London W12 0NN, UK; §Molecular Oncology, School of Biological Sciences, University of Essex, Colchester CO4 3SQ, UK;
authors.forename: Greg N
authors.initials: GN
authors.lastname: Brooke
authors.affiliation: From the ‡Androgen Signalling Laboratory, Imperial College London, London W12 0NN, UK;
authors.forename: Simon C
authors.initials: SC
authors.lastname: Gamble
authors.affiliation: §Molecular Oncology, School of Biological Sciences, University of Essex, Colchester CO4 3SQ, UK;
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hough
authors.affiliation: ¶Kennedy Institute of Rheumatology, Imperial College London, London W6 8LH, UK;
authors.forename: Shajna
authors.initials: S
authors.lastname: Begum
authors.affiliation: From the ‡Androgen Signalling Laboratory, Imperial College London, London W12 0NN, UK; ‖Cardiff University Peking University Cancer Institute, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.
authors.forename: D Alwyn
authors.initials: DA
authors.lastname: Dart
authors.affiliation: From the ‡Androgen Signalling Laboratory, Imperial College London, London W12 0NN, UK;
authors.forename: Michael
authors.initials: M
authors.lastname: Odontiadis
authors.affiliation: From the ‡Androgen Signalling Laboratory, Imperial College London, London W12 0NN, UK;
authors.forename: Sue M
authors.initials: SM
authors.lastname: Powell
authors.affiliation: From the ‡Androgen Signalling Laboratory, Imperial College London, London W12 0NN, UK;
authors.forename: Flavia M
authors.initials: FM
authors.lastname: Fioretti
authors.affiliation: §Molecular Oncology, School of Biological Sciences, University of Essex, Colchester CO4 3SQ, UK;
authors.forename: Rosie A
authors.initials: RA
authors.lastname: Bryan
authors.affiliation: From the ‡Androgen Signalling Laboratory, Imperial College London, London W12 0NN, UK;
authors.forename: Jonathan
authors.initials: J
authors.lastname: Waxman
authors.affiliation: ¶Kennedy Institute of Rheumatology, Imperial College London, London W6 8LH, UK;
authors.forename: Robin
authors.initials: R
authors.lastname: Wait
authors.affiliation: From the ‡Androgen Signalling Laboratory, Imperial College London, London W12 0NN, UK; charlotte.bevan@imperial.ac.uk.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Bevan
mesh_terms: D000595:Amino Acid Sequence; D000726:Androgen Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000813:Anilides / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D017373:Cyproterone Acetate / Q000737:chemistry / Q000494:pharmacology; D005485:Flutamide / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D058977:Molecular Sequence Annotation; D008969:Molecular Sequence Data; D009154:Mutation; D009277:Nandrolone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020543:Proteome / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism; D011944:Receptors, Androgen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014105:Tosyl Compounds / Q000737:chemistry / Q000494:pharmacology
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000813:Anilides; D009363:Neoplasm Proteins; D009570:Nitriles; D020543:Proteome; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C014290:hydroxyflutamide; D017373:Cyproterone Acetate; D009277:Nandrolone; D005485:Flutamide; C100075:mibolerone; C053541:bicalutamide