title: Role of non-genomic androgen signalling in suppressing proliferation of fibroblasts and fibrosarcoma cells.
abstract: The functions of androgen receptor (AR) in stromal cells are still debated in spite of the demonstrated importance of these cells in organ development and diseases. Here, we show that physiological androgen concentration (10 nM R1881 or DHT) fails to induce DNA synthesis, while it consistently stimulates cell migration in mesenchymal and transformed mesenchymal cells. Ten nanomolar R1881 triggers p27 Ser10 phosphorylation and its stabilization in NIH3T3 fibroblasts. Activation of Rac and its downstream effector DYRK 1B is responsible for p27 Ser10 phosphorylation and cell quiescence. Ten nanomolar androgen also inhibits transformation induced by oncogenic Ras in NIH3T3 fibroblasts. Overexpression of an AR mutant unable to interact with filamin A, use of a small peptide displacing AR/filamin A interaction, and filamin A knockdown indicate that the androgen-triggered AR/filamin A complex regulates the pathway leading to p27 Ser10 phosphorylation and cell cycle arrest. As the AR/filamin A complex is also responsible for migration stimulated by 10 nM androgen, our report shows that the androgen-triggered AR/filamin A complex controls, through Rac 1, the decision of cells to halt cell cycle and migration. This study reveals a new and unexpected role of androgen/AR signalling in coordinating stromal cell functions.
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology-II University of Naples, Via L. De Crecchio 7, 80138 Naples, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Castoria
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology-II University of Naples, Via L. De Crecchio 7, 80138 Naples, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Giovannelli
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology-II University of Naples, Via L. De Crecchio 7, 80138 Naples, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Di Donato
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology-II University of Naples, Via L. De Crecchio 7, 80138 Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Ciociola
authors.affiliation: Laboratory of Cell Biology, National Cancer Institute, Bethesda, MD 20892-4256, USA.
authors.forename: R
authors.initials: R
authors.lastname: Hayashi
authors.affiliation: Metabolism Branch, National Cancer Institute, Bethesda, MD 20892-4256, USA.
authors.forename: F
authors.initials: F
authors.lastname: Bernal
authors.affiliation: Laboratory of Cell Biology, National Cancer Institute, Bethesda, MD 20892-4256, USA.
authors.forename: E
authors.initials: E
authors.lastname: Appella
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology-II University of Naples, Via L. De Crecchio 7, 80138 Naples, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Auricchio
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology-II University of Naples, Via L. De Crecchio 7, 80138 Naples, Italy.
authors.forename: A
authors.identifier: 0000000241972055
authors.initials: A
authors.lastname: Migliaccio
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005354:Fibrosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D064448:Filamins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015741:Metribolone / Q000494:pharmacology; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D045165:Testosterone Congeners / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D000097603:Dyrk Kinases
chemical_list: D050760:Cyclin-Dependent Kinase Inhibitor p27; D013196:Dihydrotestosterone; D064448:Filamins; D015741:Metribolone; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011944:Receptors, Androgen; D012694:Serine; D045165:Testosterone Congeners; D020830:rac1 GTP-Binding Protein; D018631:ras Proteins; D000097603:Dyrk Kinases; C410798:AR protein, human; C436291:CDKN1B protein, human; C107953:RAC1 protein, human