title: Targeting androgen receptor/Src complex impairs the aggressive phenotype of human fibrosarcoma cells.
abstract: BACKGROUND
  Hormones and growth factors influence the proliferation and invasiveness of human mesenchymal tumors. The highly aggressive human fibrosarcoma HT1080 cell line harbors classical androgen receptor (AR) that responds to androgens triggering cell migration in the absence of significant mitogenesis. As occurs in many human cancer cells, HT1080 cells also express epidermal growth factor receptor (EGFR).
  
  
  METHODS
  
  
  
  RESULTS
  We report that the pure anti-androgen Casodex inhibits the growth of HT1080 cell xenografts in immune-depressed mice, revealing a novel role of AR in fibrosarcoma progression. In HT1080 cultured cells EGF, but not androgens, robustly increases DNA synthesis. Casodex abolishes the EGF mitogenic effect, implying a crosstalk between EGFR and AR. The mechanism underlying this crosstalk has been analyzed using an AR-derived small peptide, S1, which prevents AR/Src tyrosine kinase association and androgen-dependent Src activation. Present findings show that in HT1080 cells EGF induces AR/Src Association, and the S1 peptide abolishes both the assembly of this complex and Src activation. The S1 peptide inhibits EGF-stimulated DNA synthesis, cell matrix metalloproteinase-9 (MMP-9) secretion and invasiveness of HT1080 cells. Both Casodex and S1 peptide also prevent DNA synthesis and migration triggered by EGF in various human cancer-derived cells (prostate, breast, colon and pancreas) that express AR.
  
  
  CONCLUSIONS
  This study shows that targeting the AR domain involved in AR/Src association impairs EGF signaling in human fibrosarcoma HT1080 cells. The EGF-elicited processes inhibited by the peptide (DNA synthesis, MMP-9 secretion and invasiveness) cooperate in increasing the aggressive phenotype of HT1080 cells. Therefore, AR represents a new potential therapeutic target in human fibrosarcoma, as supported by Casodex inhibition of HT1080 cell xenografts. The extension of these findings in various human cancer-derived cell lines highlights the conservation of this process across divergent cancer cells and identifies new potential targets in the therapeutic approach to human cancers.
authors.affiliation: Department of Biochemistry, Biophysics, and General Pathology, 2nd University of Naples, Naples, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Castoria
authors.forename: Pia
authors.initials: P
authors.lastname: Giovannelli
authors.forename: Marzia
authors.initials: M
authors.lastname: Di Donato
authors.forename: Ryo
authors.initials: R
authors.lastname: Hayashi
authors.forename: Claudio
authors.initials: C
authors.lastname: Arra
authors.forename: Ettore
authors.initials: E
authors.lastname: Appella
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Auricchio
authors.forename: Antimo
authors.initials: A
authors.lastname: Migliaccio
mesh_terms: D000595:Amino Acid Sequence; D000726:Androgen Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000813:Anilides / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D005354:Fibrosarcoma / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use; D010641:Phenotype; D020239:Receptor Cross-Talk / Q000187:drug effects; D011944:Receptors, Androgen / Q000378:metabolism*; D014105:Tosyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C053541:bicalutamide; D019061:src-Family Kinases