Argininosuccinate lyase interacts with cyclin A2 in cytoplasm and modulates growth of liver tumor cells

doi:10.3892/or.2016.5334

CNU IR > College of Smart Living > Dept. of Senior Service and Health Management > Periodical Articles > Item 310902800/31742

Please use this identifier to cite or link to this item: https://ir.cnu.edu.tw/handle/310902800/31742

Title:	Argininosuccinate lyase interacts with cyclin A2 in cytoplasm and modulates growth of liver tumor cells
Authors:	Hung, Yu-Hsuan Huang, Hau-Lun Chen, Wei-Ching Yen, Meng-Chi Cho, Chien-Yu Weng, Tzu-Yang Wang, Chih-Yang Chen, Yi-Ling Chen, Li-Tzong Lai, Ming-Derg
Contributors:	Natl Cheng Kung Univ, Coll Med, Inst Basic Med Sci Natl Cheng Kung Univ, Coll Med, Dept Biochem & Mol Biol Natl Cheng Kung Univ, Coll Med, Ctr Infect Dis & Signaling Res Natl Hlth Res Inst, Natl Inst Canc Res Kaohsiung Med Univ,Kaohsiung Med Univ Hosp, Dept Emergency Med Chia Nan Univ Pharm & Sci, Dept Senior Citizen Serv Management Natl Hlth Res Inst, Natl Inst Canc Res
Keywords:	argininosuccinate lyase liver cancer non-enzymatic function cyclin A2 drug resistance arginine deiminase
Date:	2017-02
Issue Date:	2018-11-30 15:55:00 (UTC+8)
Publisher:	Spandidos Publ Ltd
Abstract:	Arginine is a critical amino acid in specific cancer types including hepatocellular carcinoma (HCC) and melanoma. Novel molecular mechanisms and therapeutic targets in arginine metabolism-mediated cancer formation await further identification. Our laboratory has previously demonstrated that arginine metabolic enzyme argininosuccinate lyase (ASL) promoted HCC formation in part via maintenance of cyclin A2 protein expression and arginine production for channeling to nitric oxide synthase. In this study, we investigated the mechanism by which ASL regulates cyclin A2 expression. We found that ASL interacted with cyclin A2 in HCC cells and the localization of their interaction was in the cytoplasm. Mutation of essential residues for enzymatic activity of ASL did not affect the binding of ASL to cyclin A2. Moreover, the mutant ASL retained the ability to restore the decreased tumorigenicity caused by ASL shRNA. Furthermore, overexpression of ASL conferred resistance to arginine deprivation therapy. Finally, the important pathways and potential therapeutic targets in ASL-regulated HCC were identified by bioinformatics analyses with Metacore database and Connectivity Map database. Our analyses suggested that bisoprolol, celecoxib, and ipratropium bromide, are potential therapeutics for ASL-regulated HCC formation. Thus, ASL interacts with cyclin A2 in cytoplasm, and may promote HCC formation through this non-enzymatic function. Overexpression of ASL may be a contributing factor in drug resistance for arginine deprivation therapy.
Relation:	Oncology Reports, v.37, n.2, pp.969-978
Appears in Collections:	[Dept. of Senior Service and Health Management] Periodical Articles

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