TY - JOUR
T1 - Arginine Deprivation Inhibits the Warburg Effect and Upregulates Glutamine Anaplerosis and Serine Biosynthesis in ASS1-Deficient Cancers
AU - Kremer, Jeff Charles
AU - Prudner, Bethany Cheree
AU - Lange, Sara Elaine Stubbs
AU - Bean, Gregory Richard
AU - Schultze, Matthew Bailey
AU - Brashears, Caitlyn Brook
AU - Radyk, Megan De Anna
AU - Redlich, Nathan
AU - Tzeng, Shin Cheng
AU - Kami, Kenjiro
AU - Shelton, Laura
AU - Li, Aixiao
AU - Morgan, Zack
AU - Bomalaski, John Stephen
AU - Tsukamoto, Takashi
AU - McConathy, Jon
AU - Michel, Loren Scott
AU - Held, Jason Matthew
AU - Van Tine, Brian Andrew
N1 - Publisher Copyright:
© 2017 The Author(s)
PY - 2017/1/24
Y1 - 2017/1/24
N2 - 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.
AB - 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.
KW - Warburg effect
KW - arginine
KW - arginine deprivation
KW - argininosuccinate synthetase 1
KW - cancer metabolism
KW - glutamine
KW - glutamine anaplerosis
KW - sarcoma
KW - serine
KW - serine biosynthesis
UR - http://www.scopus.com/inward/record.url?scp=85010445349&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2016.12.077
DO - 10.1016/j.celrep.2016.12.077
M3 - Article
C2 - 28122247
AN - SCOPUS:85010445349
SN - 2639-1856
VL - 18
SP - 991
EP - 1004
JO - Cell Reports
JF - Cell Reports
IS - 4
ER -