Arginine Deprivation Inhibits the Warburg Effect and Upregulates Glutamine Anaplerosis and Serine Biosynthesis in ASS1-Deficient Cancers.

Academic Article

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.
  • Published In

  • Cell Reports  Journal
  • Keywords

  • Warburg effect, arginine, arginine deprivation, argininosuccinate synthetase 1, cancer metabolism, glutamine, glutamine anaplerosis, sarcoma, serine, serine biosynthesis, Animals, Arginine, Argininosuccinate Synthase, Carrier Proteins, Cell Line, Tumor, Cell Proliferation, Citric Acid Cycle, Culture Media, Glucose, Glutaminase, Glutamine, Glycolysis, Humans, Hydrolases, Membrane Proteins, Metabolomics, Mice, Phosphoglycerate Dehydrogenase, Phosphorylation, Polyethylene Glycols, RNA Interference, Serine, Thyroid Hormones, Up-Regulation
  • Digital Object Identifier (doi)

    Author List

  • Kremer JC; Prudner BC; Lange SES; Bean GR; Schultze MB; Brashears CB; Radyk MD; Redlich N; Tzeng S-C; Kami K
  • Start Page

  • 991
  • End Page

  • 1004
  • Volume

  • 18
  • Issue

  • 4