title: The inflammatory mediator leukotriene D₄ induces subcellular β-catenin translocation and migration of colon cancer cells.
abstract: The abnormal activation of the Wnt/β-catenin pathway frequently occurs in colorectal cancer. The nuclear translocation of β-catenin activates the transcription of target genes that promote cell proliferation, survival, and invasion. The pro-inflammatory mediator leukotriene D4 (LTD4) exerts its effects through the CysLT1 receptor. We previously reported an upregulation of CysLT1R in patients with colon cancer, suggesting the importance of leukotrienes in colon cancer. The aim of this study was to investigate the impact of LTD4 on Wnt/β-catenin signaling and its effects on proliferation and migration of colon cancer cells. LTD4 stimulation led to an increase in β-catenin expression, β-catenin nuclear translocation and the subsequent transcription of MYC and CCND1. Furthermore, LTD4 significantly reduced the expression of E-cadherin and β-catenin at the plasma membrane and increased the migration and proliferation of HCT116 colon cancer cells. The effects of LTD4 can be blocked by the inhibition of CysLT1R. Furthermore, LTD4 induced the inhibition of glycogen synthase kinase 3 (GSK)-3β activity, indicating a crosstalk between the G-protein-coupled receptor CysLT1 and the Wnt/β-catenin pathway. In conclusion, LTD4, which can be secreted from macrophages and leukocytes in the tumor microenvironment, induces β-catenin translocation and the activation of β-catenin target genes, resulting in the increased proliferation and migration of colon cancer cells.
authors.affiliation: Division of Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Clinical Research Center, ;Skåne University Hospital, Malmö, Sweden.
authors.forename: Tavga
authors.initials: T
authors.lastname: Salim
authors.affiliation: Division of Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Clinical Research Center, ;Skåne University Hospital, Malmö, Sweden; Section of Surgery, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden; Bayer HealthCare, Pharmaceuticals Medical Affairs, Solna, Sweden.
authors.forename: Janna
authors.initials: J
authors.lastname: Sand-Dejmek
authors.affiliation: Division of Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Clinical Research Center, ;Skåne University Hospital, Malmö, Sweden. Electronic address: anita.sjolander@med.lu.se.
authors.forename: Anita
authors.initials: A
authors.lastname: Sjölander
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology*; D017998:Leukotriene D4 / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D013347:Subcellular Fractions; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D018836:Inflammation Mediators; D051176:beta Catenin; D017998:Leukotriene D4; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: Cell migration; Colon cancer; Inflammation; LTD(4); β-Catenin