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Cystine Induced-mTORC2 Activation through Promoting Sin1 Phosphorylation to Suppress Cancer Cell Ferroptosis.
Wang, GuoYan; Chen, Lei; Qin, SenLin; Zheng, YiNing; Xia, Chao; Yao, JunHu; Wang, Ping; Deng, Lu.
Afiliación
  • Wang G; College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China.
  • Chen L; Division of Laboratory Safety and Services, Northwest A&F University, Yangling, Shaanxi, 712100, China.
  • Qin S; College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China.
  • Zheng Y; College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China.
  • Xia C; College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China.
  • Yao J; College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China.
  • Wang P; Tongji University Cancer Center, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai, 200092, China.
  • Deng L; College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China.
Mol Nutr Food Res ; 66(23): e2200186, 2022 12.
Article en En | MEDLINE | ID: mdl-36189894
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ferroptosis / Neoplasias Idioma: En Revista: Mol Nutr Food Res Asunto de la revista: CIENCIAS DA NUTRICAO Año: 2022 Tipo del documento: Article País de afiliación: China Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ferroptosis / Neoplasias Idioma: En Revista: Mol Nutr Food Res Asunto de la revista: CIENCIAS DA NUTRICAO Año: 2022 Tipo del documento: Article País de afiliación: China Pais de publicación: Alemania