title: Inhibition of the SH3 domain-mediated binding of Src to the androgen receptor and its effect on tumor growth.
abstract: In human mammary and prostate cancer cells, steroid hormones or epidermal growth factor (EGF) trigger association of the androgen receptor (AR)-estradiol receptor (ER) (alpha or beta) complex with Src. This interaction activates Src and affects the G1 to S cell cycle progression. In this report, we identify the sequence responsible for the AR/Src interaction and describe a 10 amino-acid peptide that inhibits this interaction. Treatment of the human prostate or mammary cancer cells (LNCaP or MCF-7, respectively) with nanomolar concentrations of this peptide inhibits the androgen- or estradiol-induced association between the AR or the ER and Src the Src/Erk pathway activation, cyclin D1 expression and DNA synthesis, without interfering in the receptor-dependent transcriptional activity. Similarly, the peptide prevents the S phase entry of LNCaP and MCF-7 cells treated with EGF as well as mouse embryo fibroblasts stimulated with androgen or EGF. Interestingly, the peptide does not inhibit the S phase entry and cytoskeletal changes induced by EGF or serum treatment of AR-negative prostate cancer cell lines. The peptide is the first example of a specific inhibitor of steroid receptor-dependent signal transducing activity. The importance of these results is highlighted by the finding that the peptide strongly inhibits the growth of LNCaP xenografts established in nude mice.
authors.affiliation: Dipartimento di Patologia Generale, Facoltà di Medicina e Chirurgia, II Università di Napoli, Via L De Crecchio, Napoli, Italia.
authors.forename: A
authors.initials: A
authors.lastname: Migliaccio
authors.forename: L
authors.initials: L
authors.lastname: Varricchio
authors.forename: A
authors.initials: A
authors.lastname: De Falco
authors.forename: G
authors.initials: G
authors.lastname: Castoria
authors.forename: C
authors.initials: C
authors.lastname: Arra
authors.forename: H
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: A
authors.initials: A
authors.lastname: Ciociola
authors.forename: M
authors.initials: M
authors.lastname: Lombardi
authors.forename: R
authors.initials: R
authors.lastname: Di Stasio
authors.forename: A
authors.initials: A
authors.lastname: Barbieri
authors.forename: A
authors.initials: A
authors.lastname: Baldi
authors.forename: M V
authors.initials: MV
authors.lastname: Barone
authors.forename: E
authors.initials: E
authors.lastname: Appella
authors.forename: F
authors.initials: F
authors.lastname: Auricchio
mesh_terms: D000595:Amino Acid Sequence; D059002:Androgen Receptor Antagonists; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D010455:Peptides; D011471:Prostatic Neoplasms / Q000378:metabolism; D011485:Protein Binding; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D011959:Receptors, Estradiol / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D018909:src Homology Domains / Q000502:physiology*
chemical_list: D059002:Androgen Receptor Antagonists; D010455:Peptides; D011944:Receptors, Androgen; D011959:Receptors, Estradiol; D016392:Proto-Oncogene Proteins pp60(c-src)