title: Kynurenic acid inhibits colon cancer proliferation in vitro: effects on signaling pathways.
abstract: Kynurenic acid (KYNA), a tryptophan metabolite, inhibits proliferation of several cancer cell lines including colon cancer, renal cancer and glioblastoma cells. Previous studies reported that inhibitory properties of KYNA may be related to interactions of KYNA with cell cycle regulators and signaling proteins. However, the exact molecular interaction of KYNA with signaling pathways in colon cancer cells has not been studied to date. The molecular mechanism of KYNA activity towards colon cancer cells may be of great importance taking into consideration that KYNA is present in several tissues and physiological fluids, including gastrointestinal tract, and it is also present in various products of human diet. In this study, the inhibitory effect of KYNA on activation of phosphoinositide 3-kinase/Akt (PI3K/Akt) and mitogen-activated protein kinase (MAPK) signaling pathways in colon adenocarcinoma HT-29 cells was revealed. KYNA decreased phosphorylation of Akt, ERK 1/2 and p38 kinases in HT-29 cells. Interestingly, the study revealed also unexpected effect of KYNA on Wnt pathway in HT-29 cells. KYNA in millimolar concentrations increased protein expression of β-catenin. However, the nuclear translocation of β-catenin in HT-29 cells exposed to KYNA was not observed. Moreover, KYNA 1 mM increased antiproliferative properties of inhibitors of signaling pathways: wortmannin, PD98059, SB202190 and IWR-1. Taking into consideration these results, KYNA may be seen as a potential chemopreventive agent in colon cancer or supportive agent in standard cancer chemotherapy. However, the interactions between KYNA, Wnt signaling pathway and β-catenin need further studies to exclude potential effect of KYNA on colon carcinogenesis.
authors.affiliation: Department of Pharmacology, Medical University in Lublin, Chodźki 4a, 20-093, Lublin, Poland, walczak.ka@gmail.com.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Walczak
authors.forename: Waldemar A
authors.initials: WA
authors.lastname: Turski
authors.forename: Grażyna
authors.initials: G
authors.lastname: Rajtar
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D007736:Kynurenic Acid / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009363:Neoplasm Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D009994:Osmolar Concentration; D058539:Phosphatidylinositol 3-Kinase / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000819:agonists / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; D009363:Neoplasm Proteins; D051176:beta Catenin; D058539:Phosphatidylinositol 3-Kinase; D007736:Kynurenic Acid