Brooke, Greg N and Gamble, Simon C and Hough, Michael A and Begum, Shajna and Dart, D Alwyn and Odontiadis, Michael and Powell, Sue M and Fioretti, Flavia M and Bryan, Rosie A and Waxman, Jonathan and Wait, Robin and Bevan, Charlotte L (2015) Antiandrogens Act as Selective Androgen Receptor Modulators at the Proteome Level in Prostate Cancer Cells*. Molecular & Cellular Proteomics, 14 (5). pp. 1201-1216. DOI https://doi.org/10.1074/mcp.m113.036764
Brooke, Greg N and Gamble, Simon C and Hough, Michael A and Begum, Shajna and Dart, D Alwyn and Odontiadis, Michael and Powell, Sue M and Fioretti, Flavia M and Bryan, Rosie A and Waxman, Jonathan and Wait, Robin and Bevan, Charlotte L (2015) Antiandrogens Act as Selective Androgen Receptor Modulators at the Proteome Level in Prostate Cancer Cells*. Molecular & Cellular Proteomics, 14 (5). pp. 1201-1216. DOI https://doi.org/10.1074/mcp.m113.036764
Brooke, Greg N and Gamble, Simon C and Hough, Michael A and Begum, Shajna and Dart, D Alwyn and Odontiadis, Michael and Powell, Sue M and Fioretti, Flavia M and Bryan, Rosie A and Waxman, Jonathan and Wait, Robin and Bevan, Charlotte L (2015) Antiandrogens Act as Selective Androgen Receptor Modulators at the Proteome Level in Prostate Cancer Cells*. Molecular & Cellular Proteomics, 14 (5). pp. 1201-1216. DOI https://doi.org/10.1074/mcp.m113.036764
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.
Item Type: | Article |
---|---|
Uncontrolled Keywords: | 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 |
Subjects: | Q Science > QH Natural history > QH301 Biology |
Divisions: | Faculty of Science and Health Faculty of Science and Health > Life Sciences, School of |
SWORD Depositor: | Unnamed user with email elements@essex.ac.uk |
Depositing User: | Unnamed user with email elements@essex.ac.uk |
Date Deposited: | 23 Mar 2015 19:45 |
Last Modified: | 07 Aug 2024 19:45 |
URI: | http://repository.essex.ac.uk/id/eprint/13320 |
Available files
Filename: Brooke 2D paper 2014 revision 06-02-15 copy.pdf