title: Proliferating effect of orotic acid through mTORC1 activation mediated by negative regulation of AMPK in SK-Hep1 hepatocellular carcinoma cells.
abstract: Orotic acid (OA) is a tumor promoter of experimental liver carcinogenesis initiated by DNA reactive carcinogens, the molecular mechanisms of which have not been fully elucidated. OA increases cell proliferation and decreases apoptosis in serum-starved SK-Hep1 hepatocellular carcinoma cells, which may ascribe to the inhibition of AMP-activated protein kinase (AMPK) phosphorylation and thus activation of mammalian target of rapamycin complex 1 (mTORC1). The effects of OA on mTORC1 activation, cell proliferation, and cell-cycle progression to S and G2/M phases were completely reversed by rapamycin. Activation of AMPK by a constitutively active mutant or aminoimidazole carboxamide ribonucleotide (AICAR) rescued the effects of OA. In conclusion, OA increases the proliferation and decreases the starvation-induced apoptosis of SK-Hep1 cells via mTORC1 activation mediated by negative regulation of AMPK.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Korea.
authors.forename: Eun-Jeong
authors.initials: EJ
authors.lastname: Jung
authors.forename: Kang-Yo
authors.initials: KY
authors.lastname: Lee
authors.forename: Byung-Hoon
authors.initials: BH
authors.lastname: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009963:Orotic Acid / Q000633:toxicity*; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012265:Ribonucleotides / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
chemical_list: D046912:Multiprotein Complexes; D011506:Proteins; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D009963:Orotic Acid; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide