Context: Adrenocortical carcinoma (ACC) is a rare tumor with a very poor prognosis and no effective treatment. ACC is characterized by an increased production of IGF-II and by estrogen receptor (ER)-alpha up-regulation. Objective: The objective of this study was to define the role played by ER alpha in 17 beta-estradiol (E2)- and IGF-II-dependent ACC growth and evaluate whether selective estrogen receptor modulators are effective in controlling ACC growth in vivo. Experimental Design: The human adrenocortical cell line H295R was used as an in vitro model and to generate xenograft tumors in athymic nude mice. Results: In H295R cells IGF-II controlled expression of steroidogenic factor-1 that, in turn, increased aromatase transcription and, consequently, estrogen production, inducing cell proliferation. ER alpha silencing significantly blocked E2- and IGF-II-dependent cell proliferation. This effect was dependent on the regulation of cyclin D1 expression by ER alpha, activated in response to both E2 and IGF-II. In fact, IGF-II induced ER alpha activation by phosphorylating serine 118 and 167. Furthermore, we demonstrated that ER alpha mediated E2-induced nongenomic signaling that stimulated IGF-I receptor (IGF1R), ERK1/2, and AKT phosphorylation, resulting in a ligand-independent activation of the IGF1R-induced pathway. In addition, E2 potentiated this pathway by up-regulating IGF1R expression as a consequence of increased cAMP-responsive element binding protein activation and binding to IGF1R promoter. The estrogen antagonist, hydroxytamoxifen, the active metabolite of tamoxifen, reduced IGF1R protein levels and both E2- and IGF-II-induced cell proliferation. Moreover, H295R xenograft growth was strongly reduced by tamoxifen. Conclusion: These findings establish a critical role for ER alpha in E2- and IGF-II-dependent ACC proliferation and provide a rationale for targeting ER alpha to control the proliferation of ACC. (J Clin Endocrinol Metab 97: E2238-E2250, 2012)

Targeting estrogen receptor-α reduces adrenocortical cancer (ACC) cell growth in vitro and in vivo: Potential therapeutic role of selective estrogen receptor modulators (SERMs) for ACC treatment / Rosa, Sirianni; Fabiana, Zolea; Adele, Chimento; Carmen, Ruggiero; Cerquetti, Lidia; Francesco, Fallo; Catia, Pilon; Giorgio, Arnaldi; Giulia, Carpinelli; Stigliano, Antonio; Vincenzo, Pezzi. - In: THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM. - ISSN 0021-972X. - 97:12(2012), pp. E2238-E2250. [10.1210/jc.2012-2374]

Targeting estrogen receptor-α reduces adrenocortical cancer (ACC) cell growth in vitro and in vivo: Potential therapeutic role of selective estrogen receptor modulators (SERMs) for ACC treatment

CERQUETTI, LIDIA;STIGLIANO, Antonio;
2012

Abstract

Context: Adrenocortical carcinoma (ACC) is a rare tumor with a very poor prognosis and no effective treatment. ACC is characterized by an increased production of IGF-II and by estrogen receptor (ER)-alpha up-regulation. Objective: The objective of this study was to define the role played by ER alpha in 17 beta-estradiol (E2)- and IGF-II-dependent ACC growth and evaluate whether selective estrogen receptor modulators are effective in controlling ACC growth in vivo. Experimental Design: The human adrenocortical cell line H295R was used as an in vitro model and to generate xenograft tumors in athymic nude mice. Results: In H295R cells IGF-II controlled expression of steroidogenic factor-1 that, in turn, increased aromatase transcription and, consequently, estrogen production, inducing cell proliferation. ER alpha silencing significantly blocked E2- and IGF-II-dependent cell proliferation. This effect was dependent on the regulation of cyclin D1 expression by ER alpha, activated in response to both E2 and IGF-II. In fact, IGF-II induced ER alpha activation by phosphorylating serine 118 and 167. Furthermore, we demonstrated that ER alpha mediated E2-induced nongenomic signaling that stimulated IGF-I receptor (IGF1R), ERK1/2, and AKT phosphorylation, resulting in a ligand-independent activation of the IGF1R-induced pathway. In addition, E2 potentiated this pathway by up-regulating IGF1R expression as a consequence of increased cAMP-responsive element binding protein activation and binding to IGF1R promoter. The estrogen antagonist, hydroxytamoxifen, the active metabolite of tamoxifen, reduced IGF1R protein levels and both E2- and IGF-II-induced cell proliferation. Moreover, H295R xenograft growth was strongly reduced by tamoxifen. Conclusion: These findings establish a critical role for ER alpha in E2- and IGF-II-dependent ACC proliferation and provide a rationale for targeting ER alpha to control the proliferation of ACC. (J Clin Endocrinol Metab 97: E2238-E2250, 2012)
2012
01 Pubblicazione su rivista::01a Articolo in rivista
Targeting estrogen receptor-α reduces adrenocortical cancer (ACC) cell growth in vitro and in vivo: Potential therapeutic role of selective estrogen receptor modulators (SERMs) for ACC treatment / Rosa, Sirianni; Fabiana, Zolea; Adele, Chimento; Carmen, Ruggiero; Cerquetti, Lidia; Francesco, Fallo; Catia, Pilon; Giorgio, Arnaldi; Giulia, Carpinelli; Stigliano, Antonio; Vincenzo, Pezzi. - In: THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM. - ISSN 0021-972X. - 97:12(2012), pp. E2238-E2250. [10.1210/jc.2012-2374]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/673226
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