title: A potential anti-tumor effect of leukotriene C4 through the induction of 15-hydroxyprostaglandin dehydrogenase expression in colon cancer cells.
abstract: Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Cyclooxygenase-2, which plays a key role in the biosynthesis of prostaglandin E2 (PGE2), is often up-regulated in CRC and in other types of cancer. PGE2 induces angiogenesis and tumor cell survival, proliferation and migration. The tumor suppressor 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is a key enzyme in PGE2 catabolism, converting it into its inactive metabolite 15-keto-PGE2, and is often down-regulated in cancer. Interestingly, CRC patients expressing high levels of the cysteinyl leukotriene 2 (CysLT2) receptor have a good prognosis; therefore, we investigated a potential link between CysLT2 signaling and the tumor suppressor 15-PGDH in colon cancer cells.We observed a significant up-regulation of 15-PGDH after treatment with LTC4, a CysLT2 ligand, in colon cancer cells at both the mRNA and protein levels, which could be reduced by a CysLT2 antagonist or a JNK inhibitor. LTC4 induced 15-PGDH promoter activity via JNK/AP-1 phosphorylation. Furthermore, we also observed that LTC4, via the CysLT2/JNK signaling pathway, increased the expression of the differentiation markers sucrase-isomaltase and mucin-2 in colon cancer cells and that down-regulation of 15-PGDH totally abolished the observed increase in these markers.In conclusion, the restoration of 15-PGDH expression through CysLT2 signaling promotes the differentiation of colon cancer cells, indicating an anti-tumor effect of CysLT2 signaling.
authors.affiliation: Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Lubna M
authors.initials: LM
authors.lastname: Mehdawi
authors.affiliation: Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Shakti Ranjan
authors.initials: SR
authors.lastname: Satapathy
authors.affiliation: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Gustafsson
authors.affiliation: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Kent
authors.initials: K
authors.lastname: Lundholm
authors.affiliation: Molecular Pathology, Department of Translational Medicine, Lund University, Malmö, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Alvarado-Kristensson
authors.affiliation: Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Anita
authors.initials: A
authors.lastname: Sjölander
mesh_terms: D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000378:metabolism; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D017997:Leukotriene C4 / Q000494:pharmacology*; D018077:Receptors, Leukotriene / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018077:Receptors, Leukotriene; D017997:Leukotriene C4; C026346:15-ketoprostaglandin E2; C412375:cysteinyl leukotriene receptor 2; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D015232:Dinoprostone
keywords: 15-PGDH; CysLTR2; LTC4 signaling; anti-tumor; colon cancer