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Antiandrogens act as selective androgen receptor modulators at the proteome Level in prostate cancer cells

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Title: Antiandrogens act as selective androgen receptor modulators at the proteome Level in prostate cancer cells
Authors: Brooke, GN
Gamble, SC
Hough, MA
Begum, S
Dart, DA
Odontiadis, M
Powell, SM
Fioretti, FM
Bryan, RA
Waxman, J
Wait, R
Bevan, CL
Item Type: Journal Article
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.
Issue Date: 1-May-2015
Date of Acceptance: 1-May-2015
URI: http://hdl.handle.net/10044/1/43893
DOI: http://dx.doi.org/10.1074/mcp.M113.036764
ISSN: 1535-9484
Publisher: American Society for Biochemistry and Molecular Biology
Start Page: 1201
End Page: 1216
Journal / Book Title: Molecular & Cellular Proteomics
Volume: 14
Issue: 5
Copyright Statement: © 2015 The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version free via Creative Commons CC-BY license: https://creativecommons.org/licenses/by/3.0/
Sponsor/Funder: Prostate Cancer UK
Prostate Cancer UK
Genesis Research Trust
Prostate Cancer UK
Funder's Grant Number: IC/2004/CB/New
PG10-25
WSCC_P38565
S12-026 / PO 13182
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemical Research Methods
Biochemistry & Molecular Biology
COACTIVATOR BINDING
GENE-EXPRESSION
LNCAP CELLS
LINE LNCAP
TRANSCRIPTION ACTIVATION
REGULATED GENES
PROLIFERATION
PROHIBITIN
MUTATIONS
PROTEINS
Amino Acid Sequence
Androgen Antagonists
Anilides
Cell Line, Tumor
Cyproterone Acetate
Flutamide
Gene Expression Regulation, Neoplastic
Humans
Male
Molecular Sequence Annotation
Molecular Sequence Data
Mutation
Nandrolone
Neoplasm Proteins
Nitriles
Prostate
Proteome
Receptors, Androgen
Signal Transduction
Tosyl Compounds
Prostate
Cell Line, Tumor
Humans
Anilides
Flutamide
Tosyl Compounds
Nitriles
Nandrolone
Cyproterone Acetate
Androgen Antagonists
Neoplasm Proteins
Proteome
Receptors, Androgen
Signal Transduction
Gene Expression Regulation, Neoplastic
Amino Acid Sequence
Mutation
Molecular Sequence Data
Male
Molecular Sequence Annotation
Biochemistry & Molecular Biology
MD Multidisciplinary
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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