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Molecular Pharmacology

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Research ArticleArticle

Endothelin-1 Protects Ovarian Carcinoma Cells against Paclitaxel-Induced Apoptosis: Requirement for Akt Activation

Donatella Del Bufalo, Valeriana Di Castro, Annamaria Biroccio, Marco Varmi, Debora Salani, Laura Rosanò, Daniela Trisciuoglio, Francesca Spinella and Anna Bagnato
Molecular Pharmacology March 2002, 61 (3) 524-532; DOI: https://doi.org/10.1124/mol.61.3.524
Donatella Del Bufalo
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Valeriana Di Castro
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Annamaria Biroccio
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Marco Varmi
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Debora Salani
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Laura Rosanò
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Daniela Trisciuoglio
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Francesca Spinella
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Anna Bagnato
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Abstract

Endothelin-1 (ET-1) is a powerful mitogenic peptide produced by different tumors. In ovarian carcinoma cells, ET-1 acts as an autocrine growth factor, selectively through ETA receptor (ETAR), which is predominantly expressed in tumor cells. The aim of this study was to examine whether ET-1 plays a role in the sensitivity of three ovarian carcinoma cell lines (OVCA 433, HEY, and SK-OV-3) to apoptosis induced by two different stimuli. Our results demonstrated that the addition of ET-1 markedly inhibited serum withdrawal and paclitaxel-induced apoptosis in a concentration-dependent manner, as demonstrated by Annexin-V assay, sub-G1 peak in DNA content histograms, internucleosomal DNA fragmentation, and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick-end labeling method. Pretreatment of the cells with an ETAR antagonist, BQ 123, reversed the ET-1-induced protective effect. Paclitaxel-induced apoptosis resulted in the phosphorylation of Bcl-2 that was suppressed by the addition of ET-1. Further analysis of the signaling pathway demonstrated that ET-1 stimulated Akt activation. The phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin blocked ET-1-induced Akt phosphorylation. Inhibition of ET-1-stimulated mitogen-activated protein kinase activity did not affect ET-1 protection from paclitaxel-mediated apoptosis. Moreover, BQ 123 blocked the Akt-mediated pathway activated by ET-1, sensitizing ovarian carcinoma cells to paclitaxel treatment. These results establish a novel role for ET-1 in determining protection of ovarian carcinoma cells against paclitaxel-induced apoptosis through Bcl-2–dependent and PI3-K–mediated Akt pathways and suggest that ET-1 and ETAR could represent important targets for anticancer therapy.

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Molecular Pharmacology: 61 (3)
Molecular Pharmacology
Vol. 61, Issue 3
1 Mar 2002
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Research ArticleArticle

Endothelin-1 Protects Ovarian Carcinoma Cells against Paclitaxel-Induced Apoptosis: Requirement for Akt Activation

Donatella Del Bufalo, Valeriana Di Castro, Annamaria Biroccio, Marco Varmi, Debora Salani, Laura Rosanò, Daniela Trisciuoglio, Francesca Spinella and Anna Bagnato
Molecular Pharmacology March 1, 2002, 61 (3) 524-532; DOI: https://doi.org/10.1124/mol.61.3.524

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Research ArticleArticle

Endothelin-1 Protects Ovarian Carcinoma Cells against Paclitaxel-Induced Apoptosis: Requirement for Akt Activation

Donatella Del Bufalo, Valeriana Di Castro, Annamaria Biroccio, Marco Varmi, Debora Salani, Laura Rosanò, Daniela Trisciuoglio, Francesca Spinella and Anna Bagnato
Molecular Pharmacology March 1, 2002, 61 (3) 524-532; DOI: https://doi.org/10.1124/mol.61.3.524
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