Mouse EP3 alpha, beta, and gamma receptor variants reduce tumor cell proliferation and tumorigenesis in vivo.
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.
Macias-Perez
Ines M
IM
Department of Medicine (Division of Nephrology), Vanderbilt University, Nashville, Tennessee 37232, USA.
Zent
Roy
R
Carmosino
Monica
M
Breyer
Matthew D
MD
Breyer
Richard M
RM
Pozzi
Ambra
A
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D002449:Cell Aggregation; D002450:Cell Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048430:Cell Shape; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D018078:Receptors, Prostaglandin E / Q000235:genetics*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
C545647:PTGER3 protein, human; C545648:Ptger3 protein, mouse; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D048049:Extracellular Signal-Regulated MAP Kinases; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D020742:rhoA GTP-Binding Protein