ATF4 Regulates MYC-Mediated Neuroblastoma Cell Death upon Glutamine Deprivation

SummaryOncogenic Myc alters mitochondrial metabolism, making it dependent on exogenous glutamine (Gln) for cell survival. Accordingly, Gln deprivation selectively induces apoptosis in MYC-overexpressing cells via unknown mechanisms. Using MYCN-amplified neuroblastoma as a model, we identify PUMA, NOXA, and TRB3 as executors of Gln-starved cells. Gln depletion in MYC-transformed cells induces apoptosis through ATF4-dependent, but p53-independent, PUMA and NOXA induction. MYC-transformed cells depend on both glutamate-oxaloacetate transaminase and glutamate dehydrogenase to maintain Gln homeostasis and suppress apoptosis. Consequently, either ATF4 agonists or glutaminolysis inhibitors potently induce apoptosis in vitro and inhibit tumor growth in vivo. These results reveal mechanisms whereby Myc sensitizes cells to apoptosis, and validate ATF4 agonists and inhibitors of Gln metabolism as potential Myc-selective cancer therapeutics.

► MYCN-amplified neuroblastomas overexpress genes critical for glutamine metabolism
► PUMA, NOXA, and TRB3 are executers of Myc-mediated cell death upon glutamine deprivation
► MYCN transgenic mice treated with glutaminolysis inhibitors develop smaller tumors
► ATF4 agonists and glutaminolysis inhibitors are potential cancer therapeutics