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1.
Am J Pathol ; 176(1): 435-45, 2010 Jan.
Article in English | MEDLINE | ID: mdl-20008143

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.


Subject(s)
Calcineurin/metabolism , Calcium/metabolism , Endometrial Neoplasms/genetics , Interleukin-11/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Muscle Proteins/metabolism , NFATC Transcription Factors/metabolism , Receptors, Prostaglandin/metabolism , Aged , Cell Differentiation , Cell Proliferation , Cytokine Receptor gp130/genetics , Cytokine Receptor gp130/metabolism , DNA-Binding Proteins , Endometrial Neoplasms/pathology , Endometrium/metabolism , Endometrium/pathology , Female , Gene Expression Regulation, Neoplastic , Humans , Interleukin-11/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Middle Aged , Models, Biological , Muscle Proteins/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Interleukin-11/genetics , Receptors, Interleukin-11/metabolism
2.
Mol Hum Reprod ; 16(3): 158-69, 2010 Mar.
Article in English | MEDLINE | ID: mdl-19801577

ABSTRACT

Prokineticin-1 (PROK1) is a multifunctional secreted protein which signals via the G-protein coupled receptor, PROKR1. Previous data from our laboratory using a human genome survey microarray showed that PROK1-prokineticin receptor 1 (PROKR1) signalling regulates numerous genes important for establishment of early pregnancy, including the cytokine interleukin (IL)-11. Here, we have shown that PROK1-PROKR1 induces the expression of IL-11 in PROKR1 Ishikawa cells and first trimester decidua via the calcium-calcineurin signalling pathway in a guanine nucleotide-binding protein (G(q/11)), extracellular signal-regulated kinases, Ca(2+) and calcineurin-nuclear factor of activated T cells dependent manner. Conversely, treatment of human decidua with a lentiviral miRNA to abolish endogenous PROK1 expression results in a significant reduction in IL-11 expression and secretion. Importantly, we have also shown a regulatory role for the regulator of calcineurin 1 isoform 4 (RCAN1-4). Overexpression of RCAN1-4 in PROKR1 Ishikawa cells using an adenovirus leads to a reduction in PROK1 induced IL-11 indicating that RCAN1-4 is a negative regulator in the calcineurin-mediated signalling to IL-11. Finally, we have shown the potential for both autocrine and paracrine signalling in the human endometrium by co-localizing IL-11, IL-11Ralpha and PROKR1 within the stromal and glandular epithelial cells of non-pregnant endometrium and first trimester decidua. Overall we have identified and characterized the signalling components of a novel PROK1-PROKR1 signalling pathway regulating IL-11.


Subject(s)
Calcineurin/physiology , Gene Expression Regulation/drug effects , Interleukin-11/metabolism , NFATC Transcription Factors/physiology , Receptors, G-Protein-Coupled/physiology , Vascular Endothelial Growth Factor, Endocrine-Gland-Derived/physiology , Calcineurin/metabolism , Calcineurin Inhibitors , Cell Line, Tumor , Cyclosporine/pharmacology , Decidua/metabolism , Egtazic Acid/pharmacology , Endometrium/metabolism , Enzyme-Linked Immunosorbent Assay , Female , Flavonoids/pharmacology , Humans , Immunohistochemistry , Interleukin-11/genetics , NFATC Transcription Factors/antagonists & inhibitors , Peptides, Cyclic/pharmacology , Pregnancy , Pregnancy Trimester, First , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Vascular Endothelial Growth Factor, Endocrine-Gland-Derived/genetics , Vascular Endothelial Growth Factor, Endocrine-Gland-Derived/pharmacology
3.
Anticancer Res ; 23(4): 3199-206, 2003.
Article in English | MEDLINE | ID: mdl-12926054

ABSTRACT

BACKGROUND: Combretastatin A-4-phosphate (CA-4-P) is a microtubule depolymerising agent currently in clinical trial as a tumour vascular-targeting agent. In vivo, CA-4-P causes rapid shutdown of tumour blood flow (within minutes) and a significant neutrophil infiltration at later times. MATERIALS AND METHODS: Using an in vitro flow-cell assay, we investigated neutrophil-endothelial cell interactions and associated mechanisms, following endothelial cell exposure to CA-4-P. Cellular adhesion molecule (CAM) expression was examined using immunoblotting and immunofluorescence, and the role of CAM in neutrophil recruitment was investigated using specific blocking antibodies. RESULTS: Exposure of HUVEC to CA-4-P, resulted in significant neutrophil recruitment, and increased expression of endothelial CAM. Results of antibody studies demonstrated that endothelial CAM expression induced by CA-4-P is responsible for the observed neutrophil recruitment. DISCUSSION: This study demonstrated that the tumour vascular targeting agent, CA-4-P, directly induces endothelial CAM expression and subsequent neutrophil recruitment. In vivo, neutrophil infiltration probably contributes to CA-4-P-induced tumour cell kill. Therefore, increasing neutrophil recruitment into tumours may have potential for optimising vascular-targeted strategies for cancer therapy.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Cell Communication/drug effects , Endothelium, Vascular/drug effects , Neutrophil Infiltration/drug effects , Neutrophils/drug effects , Stilbenes/pharmacology , Cell Adhesion/drug effects , Cell Adhesion/physiology , Cell Adhesion Molecules/biosynthesis , Cell Adhesion Molecules/physiology , Cells, Cultured , Colchicine/pharmacology , Endothelium, Vascular/cytology , Humans , Neutrophils/cytology , Paclitaxel/pharmacology , Tubulin/pharmacology , Tumor Necrosis Factor-alpha/pharmacology
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