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Cell Rep. 2017 Jan 24;18(4):991-1004. doi: 10.1016/j.celrep.2016.12.077.

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

Author information

1
Division of Medical Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
2
Division of Molecular Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
3
Human Metabolome Technologies, 246-2 Mizukami Kakuganji, Tsuruoka, Yamagata 997-0052, Japan.
4
Human Metabolome Technologies America, Boston, MA 02134, USA.
5
Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
6
Polaris Pharmaceuticals, San Diego, CA 92121, USA.
7
Department of Neurology and Johns Hopkins Drug Discovery Program, Johns Hopkins University, Baltimore, MD 21205, USA.
8
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.
9
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.
10
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.
11
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.

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.

KEYWORDS:

Warburg effect; arginine; arginine deprivation; argininosuccinate synthetase 1; cancer metabolism; glutamine; glutamine anaplerosis; sarcoma; serine; serine biosynthesis

PMID:
28122247
PMCID:
PMC5840045
DOI:
10.1016/j.celrep.2016.12.077
[Indexed for MEDLINE]
Free PMC Article

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