title: Branched-chain amino acids prevent insulin-induced hepatic tumor cell proliferation by inducing apoptosis through mTORC1 and mTORC2-dependent mechanisms.
abstract: Branched-chain amino acids (BCAA) supplementation has been reported to suppress the incidence of liver cancer in obese patients with liver cirrhosis or in obese and diabetic model animals of carcinogenesis. Whether BCAA directly suppresses cell proliferation of hepatic tumor cells under hyperinsulinemic condition remain to be defined. The aim of this study was to investigate the effects of BCAA on insulin-induced proliferation of hepatic tumor cells and determine the underlying mechanisms. BCAA suppressed insulin-induced cell proliferation of H4IIE, HepG2 cells. In H4IIE cells, BCAA did not affect cell cycle progression but increased apoptosis by suppressing expressions of anti-apoptotic genes and inducing pro-apoptotic gene via inactivation of PI3K/Akt and NF-κB signaling pathways. Further studies demonstrated that BCAA inhibited PI3K/Akt pathway not only by promoting negative feedback loop from mammalian target of rapamycin complex 1 (mTORC1)/S6K1 to PI3K/Akt pathway, but also by suppressing mTORC2 kinase activity toward Akt. Our findings suggest that BCAA supplementation may be useful to suppress liver cancer progression by inhibiting insulin-induced PI3K/Akt and subsequent anti-apoptotic pathway, indicating the importance of BCAA supplementation to the obese patients with advanced liver disease.
authors.affiliation: Pharmacology, Exploratory & Applied Pharmaceutical Research Department, Pharmaceutical Research Center, Ajinomoto Pharmaceuticals Co., Ltd, Kawasaki-ku, Kawasaki-shi, Japan. asami_hagiwara@ajinomoto.com
authors.forename: Asami
authors.initials: A
authors.lastname: Hagiwara
authors.forename: Megumi
authors.initials: M
authors.lastname: Nishiyama
authors.forename: Sonoko
authors.initials: S
authors.lastname: Ishizaki
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019587:Dietary Supplements; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000597:Amino Acids, Branched-Chain; C493245:CRTC2 protein, human; D007328:Insulin; D046912:Multiprotein Complexes; D011506:Proteins; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases