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.
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Authors | A Migliaccio, L Varricchio, A De Falco, G Castoria, C Arra, H Yamaguchi, A Ciociola, M Lombardi, R Di Stasio, A Barbieri, A Baldi, M V Barone, E Appella, F Auricchio |
Journal | Oncogene
(Oncogene)
Vol. 26
Issue 46
Pg. 6619-29
(Oct 11 2007)
ISSN: 0950-9232 [Print] England |
PMID | 17486077
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Androgen Receptor Antagonists
- Peptides
- Receptors, Androgen
- Receptors, Estradiol
- Proto-Oncogene Proteins pp60(c-src)
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Topics |
- Amino Acid Sequence
- Androgen Receptor Antagonists
- Animals
- Breast Neoplasms
(metabolism)
- Humans
- Male
- Mice
- Peptides
- Prostatic Neoplasms
(metabolism)
- Protein Binding
- Proto-Oncogene Proteins pp60(c-src)
(metabolism)
- Receptors, Androgen
(metabolism)
- Receptors, Estradiol
(antagonists & inhibitors, metabolism)
- Signal Transduction
- Tumor Cells, Cultured
- src Homology Domains
(physiology)
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