Author/Authors :
Qing، نويسنده , , Guoliang and Li، نويسنده , , Bo and Vu، نويسنده , , Annette and Skuli، نويسنده , , Nicolas and Walton، نويسنده , , Zandra E. and Liu، نويسنده , , Xueyuan and Mayes، نويسنده , , Patrick A. and Wise، نويسنده , , David R. and Thompson، نويسنده , , Craig B. and Maris، نويسنده , , John M. and Hogarty، نويسنده , , Michael D. and Simon، نويسنده , , M. Celeste، نويسنده ,
Abstract :
Summary
nic 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.
