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

Yu Hsuan Hung, Hau Lun Huang, Wei Ching Chen, Meng Chi Yen, Chien Yu Cho, Tzu Yang Weng, Chih Yang Wang, Yi Ling Chen, Li Tzong Chen, Ming-Derg Lai

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)969-978
Number of pages10
JournalOncology Reports
Volume37
Issue number2
DOIs
Publication statusPublished - 2017 Feb 1

Fingerprint

Cyclin A2
Argininosuccinate Lyase
Cytoplasm
Liver
Growth
Arginine
Hepatocellular Carcinoma
Neoplasms
Celecoxib
Bisoprolol
Databases
Ipratropium
Therapeutics
Computational Biology

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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. / Argininosuccinate lyase interacts with cyclin A2 in cytoplasm and modulates growth of liver tumor cells. In: Oncology Reports. 2017 ; Vol. 37, No. 2. pp. 969-978.
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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.",
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Hung, YH, Huang, HL, Chen, WC, Yen, MC, Cho, CY, Weng, TY, Wang, CY, Chen, YL, Chen, LT & Lai, M-D 2017, 'Argininosuccinate lyase interacts with cyclin A2 in cytoplasm and modulates growth of liver tumor cells', Oncology Reports, vol. 37, no. 2, pp. 969-978. https://doi.org/10.3892/or.2016.5334

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

In: Oncology Reports, Vol. 37, No. 2, 01.02.2017, p. 969-978.

Research output: Contribution to journalArticle

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AU - Hung, Yu Hsuan

AU - Huang, Hau Lun

AU - Chen, Wei Ching

AU - Yen, Meng Chi

AU - Cho, Chien Yu

AU - Weng, Tzu Yang

AU - Wang, Chih Yang

AU - Chen, Yi Ling

AU - Chen, Li Tzong

AU - Lai, Ming-Derg

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AB - 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.

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