Scope: Mechanistic target of rapamycin (mTOR) serves as a central signaling node in the coordination of cell growth and metabolism, and it functions via two distinct complexes, namely, mTOR complex 1 (mTORC1) and mTORC2. mTORC1 plays a crucial role in sensing amino acids, whereas mTORC2 involves in sensing growth factors. However, it remains largely unclear whether mTORC2 can sense amino acids and the mechanism by which amino acids regulate mTORC2 has not been studied. Methods and results: After treating cells with indicated concentration of amino acids for different time, it is found that the mTORC2 activation is significantly increased in response to amino acids stimulation, especially cystine. Particularly, knockdown solute carrier family 7 member 11 (SLC7A11) by siRNA shows that SLC7A11-mediated cystine uptake is responsible for activating mTORC2. Mechanistically, the study finds that p38 is activated in response to cystine stimulation, and co-immunoprecipitation (Co-IP) experiments suggest that p38 regulates the assembly of components within mTORC2 by mediating the phosphorylation of the mTORC2 subunit mitogen-activated protein kinase-interacting protein 1 (Sin1) in a cystine-dependent manner. Finally, combined with inducers and inhibitors of ferroptosis and cell viability assay, the study observes that cystine-mediated regulation of the p38-Sin1-mTOR-AKT pathway induces resistance to ferroptosis. Conclusion: These results indicate that cystine-induced activation of the p38-Sin1-mTORC2-AKT pathway suppresses ferroptosis.

Evidence shows that short-chain fatty acids (SCFAs) play an important role in health maintenance and disease development. In particular, butyrate is known to induce apoptosis and autophagy. However, it remains largely unclear whether butyrate can regulate cell ferroptosis, and the mechanism by which has not been studied. In this study, we found that RAS-selective lethal compound 3 (RSL3)- and erastin-induced cell ferroptosis were enhanced by sodium butyrate (NaB). With regard to the underlying mechanism, our results showed that NaB promoted ferroptosis by inducing lipid ROS production via downregulating the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). Moreover, the FFAR2-AKT-NRF2 axis and FFAR2-mTORC1 axis accounts for the NaB-mediated downregulation of SLC7A11 and GPX4, respectively, in a cAMP-PKA-dependent manner. Functionally, we found that NaB can inhibit tumor growth and the inhibitory effect could be eliminated by administrating MHY1485 (mTORC1 activator) and Ferr-1 (ferroptosis inhibitor). Altogether, in vivo results suggest that NaB treatment is correlated to the mTOR-dependent ferroptosis and consequent tumor growth through xenografts and colitis-associated colorectal tumorigenesis, implicating the potential clinical applications of NaB for future colorectal cancer treatments. Based on all these findings, we have proposed a regulatory mechanism via which butyrate inhibits the mTOR pathway to control ferroptosis and consequent tumorigenesis.

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Scope: The mechanistic target of rapamycin complex 1 (mTORC1), as a link between nutrients and autophagy, senses many nutrients in the microenvironment. A growing body of recent literature describes the function of bile acids (BAs) as versatile signaling molecules, while it remains largely unclear whether mTORC1 can sense BAs and the mechanism has not been studied. Methods and results: After treating LO2 cells with indicated concentration of chenodeoxycholic acid (CDCA) and farnesoid X receptor (FXR) inhibitor/activator for 6 h, it finds that CDCA and FXR significantly accelerate mTORC1 activation. The results of immunofluorescence indicate that CDCA and FXR inhibit cellular autophagy through activating mTORC1 pathway. In particular, these findings show that CDCA and FXR promote the lysosomal translocation and activation of mTORC1 in an amino acid-sensitive manner. Mechanistically, the transcriptomics data indicate that SESN2 is a checkpoint for mTORC1 lysosome translocation and activation induced by FXR, and knockdown SESN2 with siRNA suppresses the regulation of FXR on autophagy. Conclusion: These results indicate that FXR-induced decrease in SESN2 expression and activation of the mTORC1 pathway can control autophagy and be explored as potential therapeutic targets for enterohepatic and metabolic disorders.