title: Taurocholate Induces Cyclooxygenase-2 Expression via the Sphingosine 1-phosphate Receptor 2 in a Human Cholangiocarcinoma Cell Line.
abstract: Cholangiocarcinoma (CCA) is a rare, but highly malignant primary hepatobiliary cancer with a very poor prognosis and limited treatment options. Our recent studies reported that conjugated bile acids (CBAs) promote the invasive growth of CCA via activation of sphingosine 1-phosphate receptor 2 (S1PR2). Cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) is the most abundant prostaglandin in various human malignancies including CCA. Previous studies have indicated that COX-2 was highly expressed in CCA tissues, and the survival rate of CCA patients was negatively associated with high COX-2 expression levels. It has also been reported that CBAs induce COX-2 expression, whereas free bile acids inhibit COX-2 expression in CCA mouse models. However, the underlying cellular mechanisms and connection between S1PR2 and COX-2 expression in CCA cells have still not been fully elucidated. In the current study, we examined the role of S1PR2 in conjugated bile acid (taurocholate, (TCA))-induced COX-2 expression in a human HuCCT1 CCA cell line and further identified the potential underlying cellular mechanisms. The results indicated that TCA-induced invasive growth of human CCA cells was correlated with S1PR2-medated up-regulation of COX-2 expression and PGE2 production. Inhibition of S1PR2 activation with chemical antagonist (JTE-013) or down-regulation of S1PR2 expression with gene-specific shRNA not only reduced COX-2 expression, but also inhibited TCA-induced activation of EGFR and the ERK1/2/Akt-NF-κB signaling cascade. In conclusion, S1PR2 plays a critical role in TCA-induced COX-2 expression and CCA growth and may represent a novel therapeutic target for CCA.
authors.affiliation: From the Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu 210009, China, the Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Runping
authors.initials: R
authors.lastname: Liu
authors.affiliation: From the Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
authors.forename: Xiaojiaoyang
authors.initials: X
authors.lastname: Li
authors.affiliation: From the Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu 210009, China, the Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Qiang
authors.affiliation: the Jiangsu Center for Pharmacodynamics Research and Evaluation, Nanjing, Jiangsu 210009, China, and.
authors.forename: Lan
authors.initials: L
authors.lastname: Luo
authors.affiliation: the Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia 23298, the McGuire Veterans Affairs Medical Center, Richmond, Virginia 23298.
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Hylemon
authors.affiliation: From the Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu 210009, China, the Jiangsu Center for Pharmacodynamics Research and Evaluation, Nanjing, Jiangsu 210009, China, and beaglejiang@cpu.edu.cn.
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: From the Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu 210009, China, the Jiangsu Center for Pharmacodynamics Research and Evaluation, Nanjing, Jiangsu 210009, China, and lyzhang@cpu.edu.cn.
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: the Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia 23298, the McGuire Veterans Affairs Medical Center, Richmond, Virginia 23298 hzhou@vcu.edu.
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000081025:Sphingosine-1-Phosphate Receptors; D013656:Taurocholic Acid / Q000494:pharmacology*
chemical_list: C471998:JTE 013; D016328:NF-kappa B; D011720:Pyrazoles; D011725:Pyridines; D049349:Receptors, Lysosphingolipid; C477522:S1PR2 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; D013656:Taurocholic Acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: bile acid; cell biology; cyclooxygenase (COX); epidermal growth factor receptor (EGFR); gene regulation; metabolism; signal transduction; sphingosine-1-phosphate (S1P)