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Vol. 61, Issue 3, 524-532, March 2002
Molecular Pathology (V.D.C., M.V., D.S., L.R., D.T., F.S., A.Ba.)
and Experimental Chemotherapy (D.D.B., A.Bi.) Laboratories, Regina
Elena Cancer Institute, Rome, Italy
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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