Branched-chain amino acids enhance premature senescence through mammalian target of rapamycin complex I-mediated upregulation of p21 protein.
Branched-chain amino acids (BCAAs) have been applied as an oral supplementation to patients with liver cirrhosis. BCAAs not only improve nutritional status of patients but also decrease the incidence of liver cancer. Mammalian target of rapamycin (mTOR) links cellular metabolism with growth and proliferation in response to nutrients, energy, and growth factors. BCAAs, especially leucine, have been shown to regulate protein synthesis through mTOR activities. On the other hand, cellular senescence is suggested to function as tumor suppressor mechanisms, and induced by a variety of stimuli including DNA damage-inducing drugs. However, it is not clear how BCAA supplementation prevents the incidence of liver cancer in patients with cirrhosis. Here we showed that human cancer cells, HepG2 and U2OS, cultured in medium containing BCAAs with Fischer's ratio about 3, which was shown to have highest activities to synthesize and secrete of albumin, had higher activities to induce premature senescence and elevate mTORC1 activities. Furthermore, BCAAs themselves enhanced the execution of premature senescence induced by DNA damage-inducing drugs, which was effectively prevented by rapamycin. These results strongly suggested the contribution of the mTORC1 pathway to the regulation of premature senescence. Interestingly, the protein levels of p21, a p53 target and well-known gene essential for the execution of cellular senescence, were upregulated in the presence of BCAAs. These results suggested that BCAAs possibly contribute to tumor suppression by enhancing cellular senescence mediated through the mTOR signalling pathway.
Biosignal Research Center, Organization of Advanced Science and Technology, Kobe University, Kobe, Japan ; Department of Biology, Graduate School of Science, Kobe University, Kobe, Japan.
Masayuki
M
Nakano
Akio
A
Nakashima
Taiki
T
Nagano
Shintaro
S
Ishikawa
Ushio
U
Kikkawa
Shinji
S
Kamada
D000597:Amino Acids, Branched-Chain / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects* / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
D000597:Amino Acids, Branched-Chain; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D058570:TOR Serine-Threonine Kinases