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1.
Mol Cell Proteomics ; 14(5): 1201-16, 2015 May.
Article in English | MEDLINE | ID: mdl-25693800

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.


Subject(s)
Androgen Antagonists/pharmacology , Gene Expression Regulation, Neoplastic , Neoplasm Proteins/isolation & purification , Prostate/drug effects , Proteome/isolation & purification , Receptors, Androgen/chemistry , Amino Acid Sequence , Androgen Antagonists/chemistry , Anilides/chemistry , Anilides/pharmacology , Cell Line, Tumor , Cyproterone Acetate/chemistry , Cyproterone Acetate/pharmacology , Flutamide/analogs & derivatives , Flutamide/chemistry , Flutamide/pharmacology , Humans , Male , Molecular Sequence Annotation , Molecular Sequence Data , Mutation , Nandrolone/analogs & derivatives , Nandrolone/chemistry , Nandrolone/pharmacology , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Nitriles/chemistry , Nitriles/pharmacology , Prostate/metabolism , Prostate/pathology , Proteome/genetics , Proteome/metabolism , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Signal Transduction , Tosyl Compounds/chemistry , Tosyl Compounds/pharmacology
2.
Oncogene ; 23(17): 2996-3004, 2004 Apr 15.
Article in English | MEDLINE | ID: mdl-14968116

ABSTRACT

Proteins involved in the growth response of prostate cancer cells to androgen were investigated by comparing the proteomes of LNCaP cells treated with vehicle or androgen. Whole-cell lysates were separated by two-dimensional PAGE, and HPLC-MS/MS was used to identify androgen-regulated proteins. Prohibitin, a protein with cell-cycle regulatory activity, was shown to be downregulated by 50% following androgen stimulation. Western blot and reverse transcription-PCR experiments confirmed the result and showed that regulation occurs at the level of transcription. To determine the importance of prohibitin in androgen-stimulated growth, we used transient transfection to overexpress the protein and RNA interference to knock down the protein. Subsequent FACS analysis showed that cells with reduced levels of prohibitin showed a slight but reproducible increase in the percentage of population in cell cycle, while cells with increased prohibitin levels showed a clear reduction in the percentage entering cell cycle, following dihydrotestosterone stimulation, when compared to untransfected controls. Confocal microscopy showed localization of prohibitin in the nucleus as well as the mitochondria of LNCaP cells. It therefore seems that the regulation of prohibitin is a vital part of the cellular growth response to androgen stimulation in LNCaPs and prohibitin may have a nuclear regulatory role in cell-cycle progression.


Subject(s)
Androgens/pharmacology , Prostatic Neoplasms/pathology , Amino Acid Sequence , Base Sequence , Cell Division/drug effects , Cell Line, Tumor , Cloning, Molecular , DNA Primers , Dihydrotestosterone/pharmacology , Electrophoresis, Gel, Two-Dimensional , Humans , Male , Molecular Sequence Data , Neoplasm Proteins/genetics , Neoplasm Proteins/isolation & purification , Peptide Fragments/chemistry , Prohibitins , RNA, Small Interfering/genetics , Repressor Proteins/genetics , Reverse Transcriptase Polymerase Chain Reaction , Transfection
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