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J. Biol. Chem., Vol. 280, Issue 16, 16311-16318, April 22, 2005

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The Oxytocin Receptor Antagonist Atosiban Inhibits Cell Growth via a "Biased Agonist" Mechanism^*

Alessandra Reversi, Valeria Rimoldi, Tiziana Marrocco, Paola Cassoni, Giovanni Bussolati, Marco Parenti¶, and Bice Chini||

From the Consiglio Nazionale delle Ricerche (CNR) Institute of Neuroscience, Cellular and Molecular Pharmacology Section, 20129 Milan, the Department of Biomedical Sciences and Human Oncology, University of Turin, 10126 Turin, and the ^¶Department of Experimental and Environmental Medicine and Medical Biotechnologies, University of Milano-Bicocca, 20052 Monza, Italy

In human myometrial cells, the promiscuous coupling of the oxytocin receptors (OTRs) to G_q and G_i leads to contraction. However, the activation of OTRs coupled to different G protein pathways can also trigger opposite cellular responses, e.g. OTR coupling to G_i inhibits, whereas its coupling to G_q stimulates, cell proliferation. Drug analogues capable of promoting a selective receptor-G protein coupling may be of great pharmacological and clinical importance because they may target only one specific signal transduction pathway. Here, we report that atosiban, an oxytocin derivative that acts as a competitive antagonist on OTR/G_q coupling, displays agonistic properties on OTR/G_i coupling, as shown by specific ³⁵S-labeled guanosine 5'-3-O-(thio) trisphosphate ([³⁵S]GTPS) binding. Moreover, atosiban, by acting on a G_i-mediated pathway_, inhibits cell growth of HEK293 and Madin-Darby canine kidney cells stably transfected with OTRs and of DU145 prostate cancer cells expressing endogenous OTRs. Notably, atosiban leads to persistent ERK1/2 activation and p21^WAF1/CIP1 induction, the same signaling events leading to oxytocin-mediated cell growth inhibition via a G_i pathway. Finally, atosiban exposure did not cause OTR internalization and led to only a modest decrease (20%) in the number of high affinity cell membrane OTRs, two observations consistent with the finding that atosiban did not lead to any desensitization of the oxytocin-induced activation of the G_q-phospholipase C pathway. Taken together, these observations indicate that atosiban acts as a "biased agonist" of the human OTRs and thus belongs to the class of compounds capable of selectively discriminating only one among the multiple possible active conformations of a single G protein-coupled receptor, thereby leading to the selective activation of a unique intracellular signal cascade.

Received for publication, August 30, 2004 , and in revised form, January 3, 2005.

^* This study was supported by a Cofin grant year 2002 (Grant 2002055453) and a FIRB grant year 2001 (Grant RBAU01XWS4) from the Italian Ministry for University and Research (to M. P.) and a Special Projet Oncology, Compagnia di San Paolo/Fondazione Internazionale di Ricerca in Medicina Sperimentale (to G. B.). 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.

^|| To whom correspondence should be addressed: CNR Institute of Neuroscience, Cellular and Molecular Pharmacology Section, Via Vanvitelli 32, 20129 Milan, Italy. Tel.: 39-02-5031 (ext. 6958); Fax: 39-02-7490574; E-mail: B.Chini{at}in.cnr.it.

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