Argininosuccinate synthetase 1 (ASS1) is a common metabolic marker of chemosensitivity for targeted arginine- and glutamine-starvation therapy

Yan Long, Wen Bin Tsai, Dajuan Wang, David H. Hawke, Niramol Savaraj, Lynn G. Feun, Mien Chie Hung, Helen H.W Chen, Macus Tien Kuo

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Argininosuccinate synthetase 1 (ASS1) is the rate-limiting enzyme that catalyzes the biosynthesis of arginine (Arg). Many malignant human tumors are auxotrophic for Arg because ASS1 is silenced. ASS1 has been established as a sensor of Arg auxotrophic response and a chemosensitivity marker for Arg starvation therapy. Here, we report that ASS1 is also a sensor for glutamine (Gln)-deprivation response, and that upregulation of ASS1 expression is associated with resistance to Gln-starvation treatments. Knockdown of ASS1 expression resulted in increased sensitivity to both Arg- and Gln-starvation, whereas increased ASS1 expression by ectopic transfection is associated with resistance to both Arg- and Gln-starvation. The addition of permeable fumarate, a metabolite that bridges the tricarboxylic acid and urea cycles, resulted in downregulation of ASS1 expression and increased sensitivity to both Arg- and Gln-deprivation treatments. Mechanistically, the Gln-deprivation response, like the arginine-auxotrophic response, downregulates HIF-1α resulting in de-silencing of ASS1. Our results demonstrate that ASS1 is a common biosensor for Arg and Gln deprivation response and a shared target for Arg- and Gln-starvation therapies which have been in several current clinical trials.

Original languageEnglish
Pages (from-to)54-63
Number of pages10
JournalCancer Letters
Volume388
DOIs
Publication statusPublished - 2017 Mar 1

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Argininosuccinate Synthase
Starvation
Glutamine
Arginine
Therapeutics
Down-Regulation
Fumarates
Citric Acid Cycle
Biosensing Techniques
Transfection
Urea
Up-Regulation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Long, Yan ; Tsai, Wen Bin ; Wang, Dajuan ; Hawke, David H. ; Savaraj, Niramol ; Feun, Lynn G. ; Hung, Mien Chie ; Chen, Helen H.W ; Kuo, Macus Tien. / Argininosuccinate synthetase 1 (ASS1) is a common metabolic marker of chemosensitivity for targeted arginine- and glutamine-starvation therapy. In: Cancer Letters. 2017 ; Vol. 388. pp. 54-63.
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Argininosuccinate synthetase 1 (ASS1) is a common metabolic marker of chemosensitivity for targeted arginine- and glutamine-starvation therapy. / Long, Yan; Tsai, Wen Bin; Wang, Dajuan; Hawke, David H.; Savaraj, Niramol; Feun, Lynn G.; Hung, Mien Chie; Chen, Helen H.W; Kuo, Macus Tien.

In: Cancer Letters, Vol. 388, 01.03.2017, p. 54-63.

Research output: Contribution to journalArticle

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AU - Long, Yan

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AU - Kuo, Macus Tien

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