The pathophysiological process ‘‘Androgen Escape’’ is a clinical phase in which the tumoral prostatic cells obtain the ability to survive and proliferate without the required signals delivered normally by circulating androgens. Androgen insensitivity reflects the ability to grow without (or with very low) circulating androgens, but it should not be confused with an absence of the intracellular signaling activated downstream of androgen binding to AR. This event occurs when the tumoral prostatic cell can over activates the androgenic pathway by several mechanisms. A convergence point of some of these pathways is the protein STAT3 (Signal Transducer and Activator of Transcription). The phosphorylation of STAT-3 of tyrosine 705 in the cytoplasm, by IL-6 and EGF, leads to its dimerization, translocation into the nucleus, DNA binding, and then, expression of genes that regulate cell proliferation, differentiation, and apoptosis. In prostate cancer (CaP) AR and STAT3 pathway are constitutively activated; they coexist in the hormone-responsive tumor and crosstalk in androgen-refractory tumor. The aim of our study was to investigate the role of STAT3 and its post-translational modifications (PTMs), like phosphorilation, acetilation, glutathionylation, responsible of a functional variability of the protein as transcription factor. To evaluate STAT3 activation and its PTMs we performed Western Blotting analysis on two human prostate cancer cell lines LNCaP, androgen-sensitive, and PC3, androgen-refractory, untreated and stimulated with IL-6 (25 ng/ml), EGF (100 ng/ml) and H2O2 (100 mM). The results showed differences between the profiles of PTMs in the two cell lines and in the different conditions. After, we examined by RT2-PCR, the expression levels of STAT3 target genes, under the same conditions: the data obtained showed a relation between PTMs of STAT3 and P21 – Signal transduction Abstracts FEBS Journal 278 (Suppl. 1) 74–445 (2011) ª 2011 The Authors Journal compilation ª 2011 Federation of European Biochemical Societies 355
Androgen-Escape": the role of STAT3 / Cocchiola, Rossana; Grillo, Caterina; Perugia, Giacomo; Chinazzi, Alessandro; Altieri, Fabio; Eufemi, Margherita. - In: THE FEBS JOURNAL. - ISSN 1742-464X. - STAMPA. - 278:1(2011), pp. 355-356. (Intervento presentato al convegno 36th FEBS Congress of the Biochemistry for Tomorrows Medicine tenutosi a Torino, ITALY nel JUN 25-30, 2011).
Androgen-Escape": the role of STAT3
COCCHIOLA, ROSSANA;GRILLO, CATERINA;PERUGIA, Giacomo;CHINAZZI, Alessandro;ALTIERI, Fabio;EUFEMI, Margherita
2011
Abstract
The pathophysiological process ‘‘Androgen Escape’’ is a clinical phase in which the tumoral prostatic cells obtain the ability to survive and proliferate without the required signals delivered normally by circulating androgens. Androgen insensitivity reflects the ability to grow without (or with very low) circulating androgens, but it should not be confused with an absence of the intracellular signaling activated downstream of androgen binding to AR. This event occurs when the tumoral prostatic cell can over activates the androgenic pathway by several mechanisms. A convergence point of some of these pathways is the protein STAT3 (Signal Transducer and Activator of Transcription). The phosphorylation of STAT-3 of tyrosine 705 in the cytoplasm, by IL-6 and EGF, leads to its dimerization, translocation into the nucleus, DNA binding, and then, expression of genes that regulate cell proliferation, differentiation, and apoptosis. In prostate cancer (CaP) AR and STAT3 pathway are constitutively activated; they coexist in the hormone-responsive tumor and crosstalk in androgen-refractory tumor. The aim of our study was to investigate the role of STAT3 and its post-translational modifications (PTMs), like phosphorilation, acetilation, glutathionylation, responsible of a functional variability of the protein as transcription factor. To evaluate STAT3 activation and its PTMs we performed Western Blotting analysis on two human prostate cancer cell lines LNCaP, androgen-sensitive, and PC3, androgen-refractory, untreated and stimulated with IL-6 (25 ng/ml), EGF (100 ng/ml) and H2O2 (100 mM). The results showed differences between the profiles of PTMs in the two cell lines and in the different conditions. After, we examined by RT2-PCR, the expression levels of STAT3 target genes, under the same conditions: the data obtained showed a relation between PTMs of STAT3 and P21 – Signal transduction Abstracts FEBS Journal 278 (Suppl. 1) 74–445 (2011) ª 2011 The Authors Journal compilation ª 2011 Federation of European Biochemical Societies 355I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
