title: Argininosuccinate synthetase 1 (ASS1) is a common metabolic marker of chemosensitivity for targeted arginine- and glutamine-starvation therapy.
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.
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Long
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Tsai
authors.affiliation: 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.
authors.forename: Dajuan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Hawke
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Niramol
authors.initials: N
authors.lastname: Savaraj
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Lynn G
authors.initials: LG
authors.lastname: Feun
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: National Cheng Kung University, National Cheng Kung University Hospital, College of Medicine, Department of Radiation Oncology, Tainan, Taiwan.
authors.forename: Helen H W
authors.initials: HH
authors.lastname: Chen
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: tkuo@mdanderson.org.
authors.forename: Macus Tien
authors.initials: MT
authors.lastname: Kuo
mesh_terms: D001120:Arginine / Q000378:metabolism*; D001124:Argininosuccinate Synthase / Q000378:metabolism*; D045744:Cell Line, Tumor; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D014162:Transfection
chemical_list: D005973:Glutamine; D001120:Arginine; D001124:Argininosuccinate Synthase
keywords: ADI-PEG20; ASS1; Arginine-starvation therapy; Glutamine-starvation therapy; HIF-1alpha and c-Myc