PMID- 36189894
OWN - NLM
STAT- MEDLINE
DCOM- 20221205
LR  - 20230117
IS  - 1613-4133 (Electronic)
IS  - 1613-4125 (Linking)
VI  - 66
IP  - 23
DP  - 2022 Dec
TI  - Cystine Induced-mTORC2 Activation through Promoting Sin1 Phosphorylation to 
      Suppress Cancer Cell Ferroptosis.
PG  - e2200186
LID - 10.1002/mnfr.202200186 [doi]
AB  - 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.
CI  - (c) 2022 Wiley-VCH GmbH.
FAU - Wang, GuoYan
AU  - Wang G
AD  - College of Animal Science and Technology, Northwest A&F University, Yangling, 
      Shaanxi, 712100, China.
FAU - Chen, Lei
AU  - Chen L
AD  - Division of Laboratory Safety and Services, Northwest A&F University, Yangling, 
      Shaanxi, 712100, China.
FAU - Qin, SenLin
AU  - Qin S
AD  - College of Animal Science and Technology, Northwest A&F University, Yangling, 
      Shaanxi, 712100, China.
FAU - Zheng, YiNing
AU  - Zheng Y
AD  - College of Animal Science and Technology, Northwest A&F University, Yangling, 
      Shaanxi, 712100, China.
FAU - Xia, Chao
AU  - Xia C
AD  - College of Animal Science and Technology, Northwest A&F University, Yangling, 
      Shaanxi, 712100, China.
FAU - Yao, JunHu
AU  - Yao J
AD  - College of Animal Science and Technology, Northwest A&F University, Yangling, 
      Shaanxi, 712100, China.
FAU - Wang, Ping
AU  - Wang P
AD  - Tongji University Cancer Center, Shanghai Tenth People's Hospital of Tongji 
      University, School of Medicine, Tongji University, Shanghai, 200092, China.
FAU - Deng, Lu
AU  - Deng L
AUID- ORCID: 0000-0002-3744-4102
AD  - College of Animal Science and Technology, Northwest A&F University, Yangling, 
      Shaanxi, 712100, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221019
PL  - Germany
TA  - Mol Nutr Food Res
JT  - Molecular nutrition & food research
JID - 101231818
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - 48TCX9A1VT (Cystine)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
SB  - IM
MH  - Mechanistic Target of Rapamycin Complex 2/metabolism
MH  - Phosphorylation
MH  - Cystine/pharmacology/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Multiprotein Complexes/chemistry/genetics/metabolism
MH  - *Ferroptosis
MH  - Adaptor Proteins, Signal Transducing/genetics
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Mechanistic Target of Rapamycin Complex 1/metabolism
MH  - *Neoplasms
OTO - NOTNLM
OT  - Sin1
OT  - cystine
OT  - ferroptosis
OT  - mTORC2
OT  - p38
EDAT- 2022/10/04 06:00
MHDA- 2022/12/06 06:00
CRDT- 2022/10/03 06:33
PHST- 2022/09/19 00:00 [revised]
PHST- 2022/03/24 00:00 [received]
PHST- 2022/10/04 06:00 [pubmed]
PHST- 2022/12/06 06:00 [medline]
PHST- 2022/10/03 06:33 [entrez]
AID - 10.1002/mnfr.202200186 [doi]
PST - ppublish
SO  - Mol Nutr Food Res. 2022 Dec;66(23):e2200186. doi: 10.1002/mnfr.202200186. Epub 
      2022 Oct 19.