Abstract

The availability of asparagine is the limitation of cell growth and metastasis. Asparagine synthetase (ASNS) was an essential enzyme for endogenous asparagine products. In our study, ASNS-induced asparagine products were essential to maintain tumor growth and colony formations in vitro. But mutated ASNS which defected endogenous asparagine products still upregulated cell invasiveness, which indicated that ASNS promoted invasiveness by alternative pathways. Mechanically, ASNS modulated Wnt signal transduction by promoting GSK3β phosphorylation on ser9 and stabilizing the β-catenin complex, as result, ASNS could promote more β-catenin translocation into nucleus independent of endogenous asparagine. At the same time, ASNS modulated mitochondrial response to Wnt stimuli with increased mitochondrial potential and membrane fusion. In summary, ASNS promoted metastasis depending on Wnt pathway and mitochondrial functions even without endogenous asparagine products.

In the Wnt pathway, phosphorylation of GSK3β(S9) is very important to stabilize β-catenin complex, ASNS can upregulate phosphorylation of AKT on Ser473, then promote GSK3β phosphorylation on Ser9 to stabilize β-catenin complex. When Wnt pathway is activated, ASNS elevates p-DRP1(637) and decreases p-DRP1(616) to suppress mitochondrial fission.

Details

Title
Asparagine synthetase regulates lung-cancer metastasis by stabilizing the β-catenin complex and modulating mitochondrial response
Author
Cai, Dong-Jing 1 ; Zhang, Zi-Yu 1 ; Bu, Yue 2 ; Li, Li 1 ; Deng, Yue-Zhen 3 ; Sun, Lun-Quan 3   VIAFID ORCID Logo  ; Hu, Cheng-Ping 4 ; Li, Min 5   VIAFID ORCID Logo 

1  Central South University, Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164); Central South University, Xiangya Lung Cancer Center, Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164) 
2  Central South University, Department of Neurology, Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164) 
3  Central South University, Xiangya Cancer Center, Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164); Key Laboratory of Molecular Radiation Oncology of Hunan Province, Changsha, China (GRID:grid.216417.7); National Clinical Research Center for Geriatric Disorders, Changsha, China (GRID:grid.216417.7) 
4  Central South University, Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164); Central South University, Xiangya Lung Cancer Center, Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164); Central South University, Xiangya Cancer Center, Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164); National Clinical Research Center for Geriatric Disorders, Changsha, China (GRID:grid.216417.7); Central South University, Center of Respiratory Medicine, Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164); Clinical Research Center for Respiratory Diseases in Hunan Province, Changsha, China (GRID:grid.216417.7) 
5  Central South University, Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164); Central South University, Xiangya Lung Cancer Center, Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164); Central South University, Xiangya Cancer Center, Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164); Key Laboratory of Molecular Radiation Oncology of Hunan Province, Changsha, China (GRID:grid.216417.7); National Clinical Research Center for Geriatric Disorders, Changsha, China (GRID:grid.216417.7); Central South University, Center of Respiratory Medicine, Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164); Clinical Research Center for Respiratory Diseases in Hunan Province, Changsha, China (GRID:grid.216417.7); Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease, Changsha, China (GRID:grid.216417.7) 
Publication year
2022
Publication date
Jun 2022
Publisher
Springer Nature B.V.
e-ISSN
20414889
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41419-022-05015-0
ProQuest document ID
2679956673
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.