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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.
AuthorsEun-Jeong Jung, Kang-Yo Lee, Byung-Hoon Lee
JournalThe Journal of toxicological sciences (J Toxicol Sci) Vol. 37 Issue 4 Pg. 813-21 ( 2012) ISSN: 1880-3989 [Electronic] Japan
PMID22863860 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Multiprotein Complexes
  • Proteins
  • Ribonucleotides
  • Aminoimidazole Carboxamide
  • Orotic Acid
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • AICA ribonucleotide
Topics
  • AMP-Activated Protein Kinases (genetics, metabolism)
  • Aminoimidazole Carboxamide (analogs & derivatives, metabolism)
  • Apoptosis (drug effects)
  • Blotting, Western
  • Cell Cycle (drug effects)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Multiprotein Complexes
  • Orotic Acid (toxicity)
  • Phosphorylation
  • Proteins (genetics, metabolism)
  • Ribonucleotides (genetics, metabolism)
  • Signal Transduction
  • TOR Serine-Threonine Kinases

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