Mouse EP3 alpha, beta, and gamma receptor variants reduce tumor cell proliferation and tumorigenesis in vivo.

Macias-Perez IM, Zent R, Carmosino M, Breyer MD, Breyer RM, Pozzi A
J Biol Chem. 2008 283 (18): 12538-45

PMID: 18230618 · PMCID: PMC2335350 · DOI:10.1074/jbc.M800105200

Prostaglandin E(2), which exerts its functions by binding to four G protein-coupled receptors (EP1-4), is implicated in tumorigenesis. Among the four E-prostanoid (EP) receptors, EP3 is unique in that it exists as alternatively spliced variants, characterized by differences in the cytoplasmic C-terminal tail. Although three EP3 variants, alpha, beta, and gamma, have been described in mice, their functional significance in regulating tumorigenesis is unknown. In this study we provide evidence that expressing murine EP3 alpha, beta, and gamma receptor variants in tumor cells reduces to the same degree their tumorigenic potential in vivo. In addition, activation of each of the three mEP3 variants induces enhanced cell-cell contact and reduces cell proliferation in vitro in a Rho-dependent manner. Finally, we demonstrate that EP3-mediated RhoA activation requires the engagement of the heterotrimeric G protein G(12). Thus, our study provides strong evidence that selective activation of each of the three variants of the EP3 receptor suppresses tumor cell function by activating a G(12)-RhoA pathway.

MeSH Terms (16)

Alternative Splicing Animals Cell Aggregation Cell Communication Cell Line, Tumor Cell Proliferation Cell Shape Enzyme Activation Extracellular Signal-Regulated MAP Kinases GTP-Binding Protein alpha Subunits, G12-G13 Humans Mice Neoplasms Receptors, Prostaglandin E Receptors, Prostaglandin E, EP3 Subtype rhoA GTP-Binding Protein

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