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.