Interleukin-11 in Endometrial Adenocarcinoma Is Regulated by Prostaglandin F-2 alpha-F-Prostanoid Receptor Interaction via the Calcium-Calcineurin-Nuclear Factor of Activated T Cells Pathway and Negatively Regulated by the Regulator of Calcineurin-1

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-11R alpha) is necessary for high-affinity binding of IL-11 to IL-11R alpha. This study investigated the expression of IL-11 and role of prostaglandin F-2 alpha-F-prostanoid receptor (FP receptor) signaling in the modulation of IL-11 expression in endometrial adenocarcinoma cells. Localization of IL-11, IL-11R alpha, and GP130 expression was performed by immunohistochemistry. IL-11 and regulator of calcineurin I 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-11R alpha, and GP130 in the neoplastic glandular epithelium of endometrial adenocarcinomas. Prostaglandin F-2 alpha-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. (Am J Pathol 2010, 176:435-445; DOI: 10.2353/ajpath.2010.090403)