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

6 Scopus citations

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 (US)
Pages (from-to)54-63
Number of pages10
JournalCancer Letters
Volume388
DOIs
StatePublished - Mar 1 2017

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Keywords

  • ADI-PEG20
  • Arginine-starvation therapy
  • ASS1
  • Glutamine-starvation therapy
  • HIF-1alpha and c-Myc

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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