title: Interleukin-11 in endometrial adenocarcinoma is regulated by prostaglandin F2alpha-F-prostanoid receptor interaction via the calcium-calcineurin-nuclear factor of activated T cells pathway and negatively regulated by the regulator of calcineurin-1.
abstract: Interleukin-11 (IL-11) up-regulates the proliferative and invasive capacity of many cancers. Coexpression of glycoprotein 130 (GP130) and IL-11 receptor alpha (IL-11Ralpha) is necessary for high-affinity binding of IL-11 to IL-11Ralpha. This study investigated the expression of IL-11 and role of prostaglandin F(2alpha)-F-prostanoid receptor (FP receptor) signaling in the modulation of IL-11 expression in endometrial adenocarcinoma cells. Localization of IL-11, IL-11Ralpha, and GP130 expression was performed by immunohistochemistry. IL-11 and regulator of calcineurin 1 isoform 4 (RCAN1-4) mRNA and protein expression were determined by real-time RT-PCR and/or enzyme-linked immunosorbent assay/Western blot analysis using Ishikawa endometrial adenocarcinoma cells stably expressing the FP receptor (FPS cells) and endometrial adenocarcinoma explants. IL-11 mRNA expression was significantly elevated in endometrial adenocarcinoma samples compared with normal endometrium and increased with tumor grade. IL-11 protein expression localized with FP receptor, IL-11Ralpha, and GP130 in the neoplastic glandular epithelium of endometrial adenocarcinomas. Prostaglandin F(2alpha)-FP receptor signaling significantly elevated the expression of IL-11 mRNA and protein in a Gq-protein kinase C-calcium-calcineurin-nuclear factor of activated T cells-dependent manner in FPS cells. The calcineurin signaling pathway is known to be controlled by the RCAN (RCAN1-4). Indeed, RCAN1-4 expression was significantly elevated in well-differentiated endometrial adenocarcinoma compared with normal endometrium and was found to decrease with tumor grade and negatively regulate IL-11 expression in vitro. This study has highlighted a new mechanism regulating IL-11 expression in endometrial adenocarcinoma cells by the FP receptor via the calcium-calcineurin-nuclear factor of activated T cells pathway.
authors.affiliation: Medical Research Council Human Reproductive Sciences Unit, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Kurt J
authors.initials: KJ
authors.lastname: Sales
authors.forename: Vivien
authors.initials: V
authors.lastname: Grant
authors.forename: Ian H
authors.initials: IH
authors.lastname: Cook
authors.forename: David
authors.initials: D
authors.lastname: Maldonado-Pérez
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
authors.forename: Alistair R W
authors.initials: AR
authors.lastname: Williams
authors.forename: Henry N
authors.initials: HN
authors.lastname: Jabbour
mesh_terms: D000368:Aged; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D004717:Endometrium / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017370:Interleukin-11 / Q000235:genetics* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D008954:Models, Biological; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053702:Receptors, Interleukin-11 / Q000235:genetics / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D017370:Interleukin-11; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; C108612:RCAN1 protein, human; D012333:RNA, Messenger; D053702:Receptors, Interleukin-11; D011982:Receptors, Prostaglandin; C034671:prostaglandin F2alpha receptor; D050822:Cytokine Receptor gp130; D019703:Calcineurin; D002118:Calcium