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

Dong-Jing Cai; Zi-Yu Zhang; Yue Bu; Li Li; Yue-Zhen Deng; Lun-Quan Sun; Cheng-Ping Hu; Min Li

doi:10.1038/s41419-022-05015-0

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

Cell Death Dis. 2022 Jun 23;13(6):566. doi: 10.1038/s41419-022-05015-0.

Authors

Dong-Jing Cai^{1

2}, Zi-Yu Zhang^{1

2}, Yue Bu³, Li Li^{1

2}, Yue-Zhen Deng^{4

5

6}, Lun-Quan Sun^{4

5

6}, Cheng-Ping Hu^{7

8

9

10

11

12}, Min Li^{13

14

15

16

17

18

19

20}

Affiliations

¹ Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, China.
² Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, China.
³ Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
⁴ Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, China.
⁵ Key Laboratory of Molecular Radiation Oncology of Hunan Province, Changsha, Hunan, China.
⁶ National Clinical Research Center for Geriatric Disorders, Changsha, China.
⁷ Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, China. huchengp28@126.com.
⁸ Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, China. huchengp28@126.com.
⁹ Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, China. huchengp28@126.com.
¹⁰ National Clinical Research Center for Geriatric Disorders, Changsha, China. huchengp28@126.com.
¹¹ Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China. huchengp28@126.com.
¹² Clinical Research Center for Respiratory Diseases in Hunan Province, Changsha, China. huchengp28@126.com.
¹³ Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, China. limin2050@csu.edu.cn.
¹⁴ Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, China. limin2050@csu.edu.cn.
¹⁵ Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, China. limin2050@csu.edu.cn.
¹⁶ Key Laboratory of Molecular Radiation Oncology of Hunan Province, Changsha, Hunan, China. limin2050@csu.edu.cn.
¹⁷ National Clinical Research Center for Geriatric Disorders, Changsha, China. limin2050@csu.edu.cn.
¹⁸ Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China. limin2050@csu.edu.cn.
¹⁹ Clinical Research Center for Respiratory Diseases in Hunan Province, Changsha, China. limin2050@csu.edu.cn.
²⁰ Hunan Engineering Research Center for Intelligent Diagnosis and Treatment of Respiratory Disease, Changsha, Hunan, China. limin2050@csu.edu.cn.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Asparagine / genetics
Aspartate-Ammonia Ligase* / genetics
Aspartate-Ammonia Ligase* / metabolism
Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor* / genetics
Cell Line, Tumor
Humans
Lung / metabolism
Lung Neoplasms* / genetics
beta Catenin / genetics

Substances

beta Catenin
Asparagine
Aspartate-Ammonia Ligase
Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor
ASNS protein, human