Arginine Deprivation Inhibits the Warburg Effect and Upregulates Glutamine Anaplerosis and Serine Biosynthesis in ASS1-Deficient Cancers.
Targeting defects in metabolism is an underutilized strategy for the treatment of cancer. Arginine auxotrophy resulting from the silencing of argininosuccinate synthetase 1 (ASS1) is a common metabolic alteration reported in a broad range of aggressive cancers. To assess the metabolic effects that arise from acute and chronic arginine starvation in ASS1-deficient cell lines, we performed metabolite profiling. We found that pharmacologically induced arginine depletion causes increased serine biosynthesis, glutamine anaplerosis, oxidative phosphorylation, and decreased aerobic glycolysis, effectively inhibiting the Warburg effect. The reduction of glycolysis in cells otherwise dependent on aerobic glycolysis is correlated with reduced PKM2 expression and phosphorylation and upregulation of PHGDH. Concurrent arginine deprivation and glutaminase inhibition was found to be synthetic lethal across a spectrum of ASS1-deficient tumor cell lines and is sufficient to cause in vivo tumor regression in mice. These results identify two synthetic lethal therapeutic strategies exploiting metabolic vulnerabilities of ASS1-negative cancers.
['Kremer|Jeff Charles|JC|', 'Prudner|Bethany Cheree|BC|', 'Lange|Sara Elaine Stubbs|SES|', 'Bean|Gregory Richard|GR|', 'Schultze|Matthew Bailey|MB|', 'Brashears|Caitlyn Brook|CB|', 'Radyk|Megan DeAnna|MD|', 'Redlich|Nathan|N|', 'Tzeng|Shin-Cheng|SC|', 'Kami|Kenjiro|K|', 'Shelton|Laura|L|', 'Li|Aixiao|A|', 'Morgan|Zack|Z|', 'Bomalaski|John Stephen|JS|', 'Tsukamoto|Takashi|T|', 'McConathy|Jon|J|', 'Michel|Loren Scott|LS|', 'Held|Jason Matthew|JM|', 'Van Tine|Brian Andrew|BA|']
D000818:Animals D001120:Arginine D001124:Argininosuccinate Synthase D002352:Carrier Proteins D045744:Cell Line, Tumor D049109:Cell Proliferation D002952:Citric Acid Cycle D003470:Culture Media D005947:Glucose D005972:Glutaminase D005973:Glutamine D006019:Glycolysis D006801:Humans D006867:Hydrolases D008565:Membrane Proteins D055432:Metabolomics D051379:Mice D050543:Phosphoglycerate Dehydrogenase D010766:Phosphorylation D011092:Polyethylene Glycols D034622:RNA Interference D012694:Serine D013963:Thyroid Hormones D015854:Up-Regulation
arginine arginine deprivation Warburg effect glutamine glutamine anaplerosis serine serine biosynthesis argininosuccinate synthetase 1 cancer metabolism sarcoma