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

Jeff Charles Kremer, Bethany Cheree Prudner, Sara Elaine Stubbs Lange, Gregory Richard Bean, Matthew Bailey Schultze, Caitlyn Brook Brashears, Megan De Anna Radyk, Nathan Redlich, Shin Cheng Tzeng, Kenjiro Kami, Laura Shelton, Aixiao Li, Zack Morgan, John Stephen Bomalaski, Takashi Tsukamoto, Jon McConathy, Loren Scott Michel, Jason Matthew Held, Brian Andrew Van Tine

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)991-1004
Number of pages14
JournalCell Reports
Volume18
Issue number4
DOIs
StatePublished - Jan 24 2017

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Kremer, J. C., Prudner, B. C., Lange, S. E. S., Bean, G. R., Schultze, M. B., Brashears, C. B., Radyk, M. D. A., Redlich, N., Tzeng, S. C., Kami, K., Shelton, L., Li, A., Morgan, Z., Bomalaski, J. S., Tsukamoto, T., McConathy, J., Michel, L. S., Held, J. M., & Van Tine, B. A. (2017). Arginine Deprivation Inhibits the Warburg Effect and Upregulates Glutamine Anaplerosis and Serine Biosynthesis in ASS1-Deficient Cancers. Cell Reports, 18(4), 991-1004. https://doi.org/10.1016/j.celrep.2016.12.077