title: Effect of prostaglandin E2 on multidrug resistance transporters in human placental cells.
abstract: Prostaglandin (PG) E2, a major product of cyclooxygenase (COX)-2, acts as an immunomodulator at the maternal-fetal interface during pregnancy. It exerts biologic function through interaction with E-prostanoid (EP) receptors localized to the placenta. The activation of the COX-2/PGE2/EP signal pathway can alter the expression of the ATP-binding cassette (ABC) transporters, multidrug resistance protein 1 [P-glycoprotein (Pgp); gene: ABCB1], and breast cancer resistance protein (BCRP; gene: ABCG2), which function to extrude drugs and xenobiotics from cells. In the placenta, PGE2-mediated changes in ABC transporter expression could impact fetal drug exposure. Furthermore, understanding the signaling cascades involved could lead to strategies for the control of Pgp and BCRP expression levels. We sought to determine the impact of PGE2 signaling mechanisms on Pgp and BCRP in human placental cells. The treatment of placental cells with PGE2 up-regulated BCRP expression and resulted in decreased cellular accumulation of the fluorescent substrate Hoechst 33342. Inhibiting the EP1 and EP3 receptors with specific antagonists attenuated the increase in BCRP. EP receptor signaling results in activation of transcription factors, which can affect BCRP expression. Although PGE2 decreased nuclear factor κ-light chain-enhancer of activated B activation and increased activator protein 1, chemical inhibition of these inflammatory transcription factors did not blunt BCRP up-regulation by PGE2. Though PGE2 decreased Pgp mRNA, Pgp expression and function were not significantly altered. Overall, these findings suggest a possible role for PGE2 in the up-regulation of placental BCRP expression via EP1 and EP3 receptor signaling cascades.
authors.affiliation: Division of Research, Department of Obstetrics and Gynecology, (C.W.M, G.T.L., Y.D., H.Z., L.H., C.P.W.), and Center for the Developmental Origins of Adult Health and Disease (C.W.M, G.T.L, Y.D., C.P.W), University of Kansas School of Medicine, Kansas City, Kansas cmason@kumc.edu.
authors.forename: Clifford W
authors.initials: CW
authors.lastname: Mason
authors.affiliation: Division of Research, Department of Obstetrics and Gynecology, (C.W.M, G.T.L., Y.D., H.Z., L.H., C.P.W.), and Center for the Developmental Origins of Adult Health and Disease (C.W.M, G.T.L, Y.D., C.P.W), University of Kansas School of Medicine, Kansas City, Kansas.
authors.forename: Gene T
authors.initials: GT
authors.lastname: Lee
authors.affiliation: Division of Research, Department of Obstetrics and Gynecology, (C.W.M, G.T.L., Y.D., H.Z., L.H., C.P.W.), and Center for the Developmental Origins of Adult Health and Disease (C.W.M, G.T.L, Y.D., C.P.W), University of Kansas School of Medicine, Kansas City, Kansas.
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Division of Research, Department of Obstetrics and Gynecology, (C.W.M, G.T.L., Y.D., H.Z., L.H., C.P.W.), and Center for the Developmental Origins of Adult Health and Disease (C.W.M, G.T.L, Y.D., C.P.W), University of Kansas School of Medicine, Kansas City, Kansas.
authors.forename: Helen
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Division of Research, Department of Obstetrics and Gynecology, (C.W.M, G.T.L., Y.D., H.Z., L.H., C.P.W.), and Center for the Developmental Origins of Adult Health and Disease (C.W.M, G.T.L, Y.D., C.P.W), University of Kansas School of Medicine, Kansas City, Kansas.
authors.forename: Lily
authors.initials: L
authors.lastname: He
authors.affiliation: Division of Research, Department of Obstetrics and Gynecology, (C.W.M, G.T.L., Y.D., H.Z., L.H., C.P.W.), and Center for the Developmental Origins of Adult Health and Disease (C.W.M, G.T.L, Y.D., C.P.W), University of Kansas School of Medicine, Kansas City, Kansas.
authors.forename: Carl P
authors.initials: CP
authors.lastname: Weiner
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D015232:Dinoprostone / Q000235:genetics* / Q000378:metabolism*; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005260:Female; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000235:genetics / Q000378:metabolism; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins; C545635:PTGER1 protein, human; C545647:PTGER3 protein, human; D012333:RNA, Messenger; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D014157:Transcription Factors; D015232:Dinoprostone