title: The cysteinyl leukotriene 2 receptor contributes to all-trans retinoic acid-induced differentiation of colon cancer cells.
abstract: BACKGROUND
  Cysteinyl leukotrienes (CysLTs) are potent pro-inflammatory mediators that are increased in samples from patients with inflammatory bowel diseases (IBDs). Individuals with IBDs have enhanced susceptibility to colon carcinogenesis. In colorectal cancer, the balance between the pro-mitogenic cysteinyl leukotriene 1 receptor (CysLT(1)R) and the differentiation-promoting cysteinyl leukotriene 2 receptor (CysLT(2)R) is lost. Further, our previous data indicate that patients with high CysLT(1)R and low CysLT(2)R expression have a poor prognosis. In this study, we examined whether the balance between CysLT(1)R and CysLT(2)R could be restored by treatment with the cancer chemopreventive agent all-trans retinoic acid (ATRA).
  
  
  METHODS
  To determine the effect of ATRA on CysLT(2)R promoter activation, mRNA level, and protein level, we performed luciferase gene reporter assays, real-time polymerase chain reactions, and Western blots in colon cancer cell lines under various conditions.
  
  
  RESULTS
  ATRA treatment induces CysLT(2)R mRNA and protein expression without affecting CysLT(1)R levels. Experiments using siRNA and mutant cell lines indicate that the up-regulation is retinoic acid receptor (RAR) dependent. Interestingly, ATRA also up-regulates mRNA expression of leukotriene C4 synthase, the enzyme responsible for the production of the ligand for CysLT(2)R. Importantly, ATRA-induced differentiation of colorectal cancer cells as shown by increased expression of MUC-2 and production of alkaline phosphatase, both of which could be reduced by a CysLT(2)R-specific inhibitor.
  
  
  CONCLUSIONS
  This study identifies a novel mechanism of action for ATRA in colorectal cancer cell differentiation and demonstrates that retinoids can have anti-tumorigenic effects through their action on the cysteinyl leukotriene pathway.
authors.affiliation: Astrid Friborg at Berries by Astrid, Stockholm, Sweden.
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Bengtsson
authors.forename: Gunilla
authors.initials: G
authors.lastname: Jönsson
authors.forename: Cecilia
authors.initials: C
authors.lastname: Magnusson
authors.forename: Tavga
authors.initials: T
authors.lastname: Salim
authors.forename: Cecilia
authors.initials: C
authors.lastname: Axelsson
authors.forename: Anita
authors.initials: A
authors.lastname: Sjölander
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006801:Humans; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D018077:Receptors, Leukotriene / Q000096:biosynthesis*; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D018077:Receptors, Leukotriene; D014212:Tretinoin; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor