Methionine Protects Mammary Cells against Oxidative Stress through Producing S-Adenosylmethionine to Maintain mTORC1 Signaling Activity

The mechanistic target of rapamycin complex 1 (mTORC1) signaling plays pivotal roles in cell growth and diseases. However, it remains mechanistically unclear about how to maintain mTORC1 activity during mammary glands development. Here we showed that mammary glands suffered from aggravated oxidative stress as pregnancy advanced and was accompanied by an increase in H(2)O(2) levels, while the consumption for methionine and S-adenosylmethionine (SAM) rather than S-adenosylhomocysteine (SAH) were promoted in vivo. Likewise, H(2)O(2) promoted SAM synthesis and reduced SAM utilization for methylation depending on H(2)O(2) levels and treatment time in vitro. H(2)O(2) inhibited phosphorylation of S6 kinase Thr 389 (p-S6K1 (T389)), 4E-BP1 Thr 37/46 and ULK1 Ser 757, the downstream of mTORC1, in mammary epithelial cells. However, methionine and SAM were shown to activate mTORC1 under H(2)O(2)-exposed condition. Moreover, this effect was not disabled by SGI-1027 which inhibits SAM transmethylation. In conclusion, methionine appeared to protect mammary cells against oxidative stress through producing SAM to maintain mTORC1 signaling activity.