Asparagine synthetase regulates lung-cancer metastasis by stabilizing the β-catenin complex and modulating mitochondrial response

• DOI: 10.1038/s41419-022-05015-0
• Publication Date: 2022-06-23T15:04:16Z
• Authors: Dong-Jing Cai; Zi-Yu Zhang; Yue Bu; Li Li; Yue-Zhen Deng; Lun-Quan Sun; Cheng-Ping Hu; Min Li
• Keywords: 0303 health sciences; Lung Neoplasms; QH573-671; Aspartate-Ammonia Ligase; Article; 03 medical and health sciences; Cell Line, Tumor; Humans; Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor; Asparagine; Cytology; Lung; beta Catenin

AbstractThe 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.