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 - Feb 1 2017
Externally publishedYes

Keywords

  • Arginine deiminase
  • Argininosuccinate lyase
  • Cyclin A2
  • Drug resistance
  • Liver cancer
  • Non-enzymatic function

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Hung, Y. H., Huang, H. L., Chen, W. C., Yen, M. C., Cho, C. Y., Weng, T. Y., Wang, C. Y., Chen, Y. L., Chen, L. T., & Lai, M. D. (2017). Argininosuccinate lyase interacts with cyclin A2 in cytoplasm and modulates growth of liver tumor cells. Oncology Reports, 37(2), 969-978. https://doi.org/10.3892/or.2016.5334