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Cancer Lett. 2017 Mar 1;388:54-63. doi: 10.1016/j.canlet.2016.11.028. Epub 2016 Nov 30.

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

Author information

1
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
2
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, PR China.
3
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
4
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
5
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
6
National Cheng Kung University, National Cheng Kung University Hospital, College of Medicine, Department of Radiation Oncology, Tainan, Taiwan.
7
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: tkuo@mdanderson.org.

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.

KEYWORDS:

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

PMID:
27913198
DOI:
10.1016/j.canlet.2016.11.028
[Indexed for MEDLINE]

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