title: Arginine Deprivation Inhibits the Warburg Effect and Upregulates Glutamine Anaplerosis and Serine Biosynthesis in ASS1-Deficient Cancers.
abstract: 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.
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jeff Charles
authors.initials: JC
authors.lastname: Kremer
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Bethany Cheree
authors.initials: BC
authors.lastname: Prudner
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sara Elaine Stubbs
authors.initials: SES
authors.lastname: Lange
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Gregory Richard
authors.initials: GR
authors.lastname: Bean
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Matthew Bailey
authors.initials: MB
authors.lastname: Schultze
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Caitlyn Brook
authors.initials: CB
authors.lastname: Brashears
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Megan DeAnna
authors.initials: MD
authors.lastname: Radyk
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Redlich
authors.affiliation: Division of Molecular Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Shin-Cheng
authors.initials: SC
authors.lastname: Tzeng
authors.affiliation: Human Metabolome Technologies, 246-2 Mizukami Kakuganji, Tsuruoka, Yamagata 997-0052, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kami
authors.affiliation: Human Metabolome Technologies America, Boston, MA 02134, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Shelton
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Aixiao
authors.initials: A
authors.lastname: Li
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Zack
authors.initials: Z
authors.lastname: Morgan
authors.affiliation: Polaris Pharmaceuticals, San Diego, CA 92121, USA.
authors.forename: John Stephen
authors.initials: JS
authors.lastname: Bomalaski
authors.affiliation: Department of Neurology and Johns Hopkins Drug Discovery Program, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsukamoto
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Radiology, University of Alabama, Birmingham, AL 35249, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: McConathy
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Loren Scott
authors.initials: LS
authors.lastname: Michel
authors.affiliation: Division of Molecular Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jason Matthew
authors.initials: JM
authors.lastname: Held
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: bvantine@wustl.edu.
authors.forename: Brian Andrew
authors.initials: BA
authors.lastname: Van Tine
mesh_terms: D000818:Animals; D001120:Arginine / Q000737:chemistry; D001124:Argininosuccinate Synthase / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002952:Citric Acid Cycle / Q000187:drug effects; D003470:Culture Media / Q000737:chemistry / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D005972:Glutaminase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism* / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D006867:Hydrolases / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D055432:Metabolomics; D051379:Mice; D050543:Phosphoglycerate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011092:Polyethylene Glycols / Q000494:pharmacology; D034622:RNA Interference; D012694:Serine / Q000096:biosynthesis*; D013963:Thyroid Hormones / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D001120:Arginine; D001124:Argininosuccinate Synthase; D002352:Carrier Proteins; D003470:Culture Media; D005947:Glucose; D005972:Glutaminase; D005973:Glutamine; D006867:Hydrolases; D008565:Membrane Proteins; D050543:Phosphoglycerate Dehydrogenase; D011092:Polyethylene Glycols; D012694:Serine; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C512527:ADI PEG20
keywords: Warburg effect; arginine; arginine deprivation; argininosuccinate synthetase 1; cancer metabolism; glutamine; glutamine anaplerosis; sarcoma; serine; serine biosynthesis