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Inhibition of the SH3 domain-mediated binding of Src to the androgen receptor and its effect on tumor growth

Oncogene volume 26, pages 6619–6629 (2007)Cite this article

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) (α or β) 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.

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Abbreviations

BrdU:

bromodeoxyuridine

EGF:

epidermal growth factor

EGFR:

epidermal growth factor receptor

ER:

estradiol receptor

hAR:

human androgen receptor

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Acknowledgements

We thank F Claessens for 3416 ARE-Luc construct, A Belfiore for AR-negative PC3 and DU145 cells and L Altucci for ERE-luc construct. Zeneca (Italy) provided the antiestrogen ICI 182,780 and Casodex. The technical assistance of Flavia Vitale is also acknowledged. This research was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC), the Ministero dell'Università e della Ricerca Scientifica (Cofin 2006), and the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.

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Authors and Affiliations

  1. Dipartimento di Patologia Generale, Facoltà di Medicina e Chirurgia, II Università di Napoli, Via L De Crecchio, Napoli, Italia

    A Migliaccio, L Varricchio, A De Falco, G Castoria, A Ciociola, M Lombardi, R Di Stasio & F Auricchio

  2. Istituto per la Cura dei Tumori – Fondazione ‘G Pascale’, Napoli, Italia

    C Arra & A Barbieri

  3. Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MA, USA

    H Yamaguchi & E Appella

  4. Dipartimento di Biochimica e Biofisica ‘F Cedrangolo’, Sezione di Anatomia Patologica, II Università di Napoli, Napoli, Italia

    A Baldi

  5. Dipartimento di Pediatria, Facolta' di Medicina e Chirurgia, Universita' di Napoli Federico II, Napoli, Italia

    M V Barone

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  1. A Migliaccio
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  2. L Varricchio
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  3. A De Falco
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  4. G Castoria
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  5. C Arra
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  6. H Yamaguchi
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  7. A Ciociola
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  8. M Lombardi
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  9. R Di Stasio
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  10. A Barbieri
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  11. A Baldi
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  12. M V Barone
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  13. E Appella
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  14. F Auricchio
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Corresponding author

Correspondence to F Auricchio.

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Migliaccio, A., Varricchio, L., De Falco, A. et al. Inhibition of the SH3 domain-mediated binding of Src to the androgen receptor and its effect on tumor growth. Oncogene 26, 6619–6629 (2007). https://doi.org/10.1038/sj.onc.1210487

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  • DOI: https://doi.org/10.1038/sj.onc.1210487

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