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  • Title: The androgen receptor and prostate cancer invasion.
    Author: Bonaccorsi L, Muratori M, Marchiani S, Forti G, Baldi E.
    Journal: Mol Cell Endocrinol; 2006 Feb 26; 246(1-2):157-62. PubMed ID: 16376012.
    Abstract:
    Recent evidence indicates that androgen-sensitive prostate cancer cells are characterized by a less pronounced malignant phenotype. We demonstrate that transfection with an androgen receptor (AR) expression vector of the androgen-independent (AI) prostate cancer cell line PC3 decreases invasion and adhesion of these cells through modulation of alpha6beta4 integrin expression. Treatment of PC3-AR cells with the synthetic androgen R1881 further reduced invasion without modifying alpha6beta4 expression on the cell surface, suggesting interference with the invasion process in response to EGF by an alternative mechanism. We investigated EGF-induced auto-transphosphorylation of EGFR in both cell lines. We found that EGFR auto-transphosphorylation was reduced in PC3-AR cells and was further decreased by administration of androgens. Since auto-transphosphorylation regulates many different functions of EGFR, including docking of kinases, ubiquitination and internalization, we next investigated all these processes in PC3-AR cells. EGF-stimulated PI3K activity, a key signalling pathway for invasion of these cells, was decreased in PC3-AR cells and further reduced by treatment with R1881. Interestingly, EGFR-PI3K interaction was also disrupted in these cells. Furthermore, EGFR ubiquitination and internalization were found to be reduced in PC3-AR cells both in basal conditions and following treatment with androgens. According to recent findings, an endocytotic pathway may be important for EGFR signalling by controlling the specificity of the response. By using immunoconfocal fluorescent microscopy, we demonstrated that AR in PC3 cells is mainly located in cytoplasm and transmigrates in part to the nucleus following stimulation with androgens. Interestingly, immunoconfocal and immunoprecipitation experiments demonstrated also the occurrence of co-localization and interaction of AR with EGFR in PC3-AR cells and in another androgen-dependent PC cell line, LNCaP. We hypothesize a mechanism by which, through direct interaction with EGFR, the AR elicits a reduction of EGF-mediated signalling and confers a less malignant phenotype.
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