Role of non-genomic androgen signalling in suppressing proliferation of fibroblasts and fibrosarcoma cells

• Published in: Cell death & disease Vol. 5; no. 12; p. e1548
• Main Authors: Castoria, G, Giovannelli, P, Di Donato, M, Ciociola, A, Hayashi, R, Bernal, F, Appella, E, Auricchio, F, Migliaccio, A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2014; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/136/2091; 631/67/1798; 631/80/84; 631/80/86; 82/29; 96/1; 96/109; 96/95; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Cycle Checkpoints - drug effects; Cell Movement - drug effects; Cell Proliferation - drug effects; Cyclin-Dependent Kinase Inhibitor p27 - genetics; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Dihydrotestosterone - pharmacology; Dyrk Kinases; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibrosarcoma - genetics; Fibrosarcoma - metabolism; Fibrosarcoma - pathology; Filamins - genetics; Filamins - metabolism; Gene Expression Regulation; Humans; Immunology; Life Sciences; Male; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - metabolism; Metribolone - pharmacology; Mice; NIH 3T3 Cells; Original; original-article; Phosphorylation; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; ras Proteins - genetics; ras Proteins - metabolism; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Serine - metabolism; Signal Transduction; Testosterone Congeners - pharmacology; Tumor Cells, Cultured
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.497

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.