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

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

来源：Cell Reports, 2017, 18(4): 991-1004.

DOI：10.1016/j.celrep.2016.12.077

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.

• 出版日期2017-1-24