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 a...

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Published in:	Cell reports (Cambridge) 2017-01, Vol.18 (4), p.991-1004
Main Authors:	Kremer, Jeff Charles, Prudner, Bethany Cheree, Lange, Sara Elaine Stubbs, Bean, Gregory Richard, Schultze, Matthew Bailey, Brashears, Caitlyn Brook, Radyk, Megan DeAnna, Redlich, Nathan, Tzeng, Shin-Cheng, Kami, Kenjiro, Shelton, Laura, Li, Aixiao, Morgan, Zack, Bomalaski, John Stephen, Tsukamoto, Takashi, McConathy, Jon, Michel, Loren Scott, Held, Jason Matthew, Van Tine, Brian Andrew
Format:	Article
Language:	eng
Subjects:	Animals arginine Arginine - chemistry arginine deprivation Argininosuccinate Synthase - genetics Argininosuccinate Synthase - metabolism argininosuccinate synthetase 1 cancer metabolism Carrier Proteins - metabolism Cell Line, Tumor Cell Proliferation - drug effects Citric Acid Cycle - drug effects Culture Media - chemistry Culture Media - pharmacology Glucose - metabolism Glucose - pharmacology Glutaminase - antagonists & inhibitors Glutaminase - genetics Glutaminase - metabolism glutamine Glutamine - metabolism Glutamine - pharmacology glutamine anaplerosis Glycolysis - drug effects Humans Hydrolases - pharmacology Membrane Proteins - metabolism Metabolomics Mice Phosphoglycerate Dehydrogenase - genetics Phosphoglycerate Dehydrogenase - metabolism Phosphorylation - drug effects Polyethylene Glycols - pharmacology RNA Interference sarcoma serine Serine - biosynthesis Thyroid Hormone-Binding Proteins Thyroid Hormones - metabolism Up-Regulation - drug effects Warburg effect
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Summary:	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. [Display omitted] •ADI-PEG20 upregulates glutamine anaplerosis and oxidative phosphorylation•Targeting glutamine metabolism with ADI-PEG20 induces synthetic lethality•Arginine deprivation causes ASS1 deficient cells to upregulate serine biosynthesis•Acquired resistance to ADI-PEG20 sensitizes to inhibition of serine metabolism Using global metabolomics analysis and stable isotope tracing, Kremer et al. show that arginine starvation of ASS1-deficient tumors causes an increase in serine biosynthesis, glutamine anaplerosis, and oxidative phosphorylation with a simultaneous decrease in aerobic glycolysis. Pharmacological inhibition of escape pathways to arginine deprivation exhibits a synthetic lethal interaction.
ISSN:	2211-1247 2211-1247