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 Rosanï, Daniela Trisciuoglio, Francesca Spinella, Anna Bagnato

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)524-532
Number of pages9
JournalMolecular Pharmacology
Volume61
Issue number3
DOIs
Publication statusPublished - 2002

ASJC Scopus subject areas

  • Pharmacology

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