title: Androgen-induced cell migration: role of androgen receptor/filamin A association.
abstract: BACKGROUND
  Androgen receptor (AR) controls male morphogenesis, gametogenesis and prostate growth as well as development of prostate cancer. These findings support a role for AR in cell migration and invasiveness. However, the molecular mechanism involved in AR-mediated cell migration still remains elusive.
  
  
  RESULTS
  Mouse embryo NIH3T3 fibroblasts and highly metastatic human fibrosarcoma HT1080 cells harbor low levels of transcriptionally incompetent AR. We now report that, through extra nuclear action, AR triggers migration of both cell types upon stimulation with physiological concentrations of the androgen R1881. We analyzed the initial events leading to androgen-induced cell migration and observed that challenging NIH3T3 cells with 10 nM R1881 rapidly induces interaction of AR with filamin A (FlnA) at cytoskeleton. AR/FlnA complex recruits integrin beta 1, thus activating its dependent cascade. Silencing of AR, FlnA and integrin beta 1 shows that this ternary complex controls focal adhesion kinase (FAK), paxillin and Rac, thereby driving cell migration. FAK-null fibroblasts migrate poorly and Rac inhibition by EHT impairs motility of androgen-treated NIH3T3 cells. Interestingly, FAK and Rac activation by androgens are independent of each other. Findings in human fibrosarcoma HT1080 cells strengthen the role of Rac in androgen signaling. The Rac inhibitor significantly impairs androgen-induced migration in these cells. A mutant AR, deleted of the sequence interacting with FlnA, fails to mediate FAK activation and paxillin tyrosine phosphorylation in androgen-stimulated cells, further reinforcing the role of AR/FlnA interaction in androgen-mediated motility.
  
  
  CONCLUSIONS
  The present report, for the first time, indicates that the extra nuclear AR/FlnA/integrin beta 1 complex is the key by which androgen activates signaling leading to cell migration. Assembly of this ternary complex may control organ development and prostate cancer metastasis.
authors.affiliation: Dipartimento di Patologia Generale, II Università di Napoli, Napoli, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Castoria
authors.forename: Loredana
authors.initials: L
authors.lastname: D'Amato
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ciociola
authors.forename: Pia
authors.initials: P
authors.lastname: Giovannelli
authors.forename: Tiziana
authors.initials: T
authors.lastname: Giraldi
authors.forename: Leandra
authors.initials: L
authors.lastname: Sepe
authors.forename: Giovanni
authors.initials: G
authors.lastname: Paolella
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Barone
authors.forename: Antimo
authors.initials: A
authors.lastname: Migliaccio
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Auricchio
mesh_terms: D041721:3T3-L1 Cells; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D019556:COS Cells; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003285:Contractile Proteins / Q000378:metabolism* / Q000502:physiology*; D064448:Filamins; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism / Q000502:physiology; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism* / Q000502:physiology*; D041681:NIH 3T3 Cells; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011944:Receptors, Androgen / Q000378:metabolism* / Q000502:physiology*
chemical_list: D000728:Androgens; D003285:Contractile Proteins; D064448:Filamins; D019012:Integrin beta1; D008840:Microfilament Proteins; D011944:Receptors, Androgen; D015741:Metribolone