title: Alpha-ketoglutarate (AKG) inhibits proliferation of colon adenocarcinoma cells in normoxic conditions.
abstract: OBJECTIVE
  Alpha-ketoglutarate (AKG), a key intermediate in Krebs cycle, is an important biological compound involved in the formation of amino acids, nitrogen transport, and oxidation reactions. AKG is already commercially available as a dietary supplement and its supplementation with glutamine, arginine, or ornithine alpha-ketoglutarate has been recently considered to improve anticancer immune functions. It is well documented that AKG treatment of Hep3B hepatoma cells in hypoxia induced HIF-alpha (hypoxia-inducible factor) degradation and reduced vascular endothelial growth factor (VEGF) synthesis. Moreover, AKG showed potent antitumor effects in murine tumor xenograft model, inhibiting tumor growth, angiogenesis, and VEGF gene expression. However, the mechanisms of its anticancer activity in normoxia have not been examined so far.
  
  
  RESULTS
  Here, we report that in normoxia, AKG inhibited proliferation of colon adenocarcinoma cell lines: Caco-2, HT-29, and LS-180, representing different stages of colon carcinogenesis. Furthermore, AKG influenced the cell cycle, enhancing the expression of the inhibitors of cyclin-dependent kinases p21 Waf1/Cip1 and p27 Kip1. Moreover, expression of cyclin D1, required in G1/S transmission, was decreased, which accompanied with the significant increase in cell number in G1 phase. AKG affected also one the key cell cycle regulator, Rb, and reduced its activation status.
  
  
  CONCLUSIONS
  In this study for the first time, the antiproliferative activity of AKG on colon adenocarcinoma Caco-2, HT-29, and LS-180 cells in normoxic conditions was revealed. Taking into consideration an anticancer activity both in hypoxic and normoxic conditions, AKG may be considered as a new potent chemopreventive agent.
authors.affiliation: Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Skłodowska University, Akademicka, Lublin, Poland. rzeskiw@hektor.umcs.lublin.pl
authors.forename: Wojciech
authors.initials: W
authors.lastname: Rzeski
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Walczak
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Juszczak
authors.forename: Ewa
authors.initials: E
authors.lastname: Langner
authors.forename: Piotr
authors.initials: P
authors.lastname: Pożarowski
authors.forename: Martyna
authors.initials: M
authors.lastname: Kandefer-Szerszeń
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Pierzynowski
mesh_terms: D018938:Caco-2 Cells; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000187:drug effects / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000187:drug effects / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000187:drug effects / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D007656:Ketoglutaric Acids / Q000494:pharmacology*; D010100:Oxygen; D010766:Phosphorylation / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007656:Ketoglutaric Acids; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D010100:Oxygen