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J. Biol. Chem., Vol. 278, Issue 42, 41294-41301, October 17, 2003

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Endothelin-1 Decreases Gap Junctional Intercellular Communication by Inducing Phosphorylation of Connexin 43 in Human Ovarian Carcinoma Cells^*

Francesca Spinella , Laura Rosanò, Valeriana Di Castro, Maria Rita Nicotra , Pier Giorgio Natali ¶ and Anna Bagnato ||

From the Laboratories of Molecular Pathology and Ultrastructure and ^¶Immunology, Regina Elena Cancer Institute, Rome 00158, Italy and the Institute of Molecular Biology and Pathology, National Research Council, Rome 00137, Italy

Endothelin-1 (ET-1) is overexpressed in ovarian carcinoma and acts as an autocrine factor selectively through the ET_A receptor (ET_AR) to promote tumor cell proliferation, survival, neovascularization, and invasiveness. Loss of gap junctional intercellular communication (GJIC) is critical for tumor progression by allowing the cells to escape growth control. Exposure of HEY and OVCA 433 ovarian carcinoma cell lines to ET-1 led to a 50–75% inhibition in intercellular communication and to a decrease in the connexin 43 (Cx43)-based gap junction plaques. To investigate the phosphorylation state of Cx43, ovarian carcinoma cell lysates were immunoprecipitated and transient tyrosine phosphorylation of Cx43 was detected in ET-1-treated cells. BQ 123, a selective ET_AR antagonist, blocked the ET-1-induced Cx43 phosphorylation and cellular uncoupling. Gap junction closure was prevented by tyrphostin 25 and by the selective c-Src inhibitor, PP2. Furthermore, the increased Cx43 tyrosine phosphorylation was correlated with ET-1-induced increase of c-Src activity, and PP2 suppressed the ET-1-induced Cx43 tyrosine phosphorylation, indicating that inhibition of Cx43-based GJIC is mainly mediated by the Src tyrosine kinase pathway. In vivo, the inhibition of human ovarian tumor growth in nude mice induced by the potent ET_AR antagonist, ABT-627, was associated with a reduction of Cx43 phosphorylation. These findings indicate that the signaling mechanisms involved in GJIC disruption on ovarian carcinoma cells depend on ET_AR activation, which leads to the Cx43 tyrosine phosphorylation mediated by c-Src, suggesting that ET_AR blockade may contribute to the control of ovarian carcinoma growth and progression also by preventing the loss of GJIC.

Received for publication, May 7, 2003 , and in revised form, August 1, 2003.

^* This work was supported by grants from the Associazione Italiana Ricerca sul Cancro, from Ministero della Salute, and from MIUR-Consiglio Nazionale delle Ricerche. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a fellowship from Fondazione Italiana Ricerca sul Cancro.

^|| To whom correspondence and reprint requests should be addressed: Laboratory of Molecular Pathology and Ultrastructure, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, Rome 00158, Italy. Tel.: 39-06-52662565; Fax: 39-06-52662505; E-mail: bagnato{at}ifo.it.

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