ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation Journal Article
| Authors: | Qing, G.; Li, B.; Vu, A.; Skuli, N.; Walton, Z. E.; Liu, X.; Mayes, P. A.; Wise, D. R.; Thompson, C. B.; Maris, J. M.; Hogarty, M. D.; Simon, M. C. |
| Article Title: | ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation |
| Abstract: | Oncogenic 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. © 2012 Elsevier Inc. |
| Keywords: | controlled study; human cell; proto-oncogene proteins; nonhuman; cell proliferation; mouse; animals; cell cycle proteins; mice; apoptosis; animal experiment; animal model; apoptosis regulatory proteins; in vivo study; in vitro study; caspases; protein p53; mice, inbred balb c; aspartate aminotransferase; mice, nude; neuroblastoma; cell transformation; protein-serine-threonine kinases; myc protein; protein induction; tumor suppressor protein p53; epigallocatechin gallate; tumor growth; homeostasis; proto-oncogene proteins c-myc; repressor proteins; proto-oncogene proteins c-bcl-2; activating transcription factor 4; glutamine; puma protein; fenretinide; glutamate dehydrogenase; bcl-2-associated x protein; amino acid metabolism; protein noxa; aminooxyacetic acid |
| Journal Title: | Cancer Cell |
| Volume: | 22 |
| Issue: | 5 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2012-11-13 |
| Start Page: | 631 |
| End Page: | 644 |
| Language: | English |
| DOI: | 10.1016/j.ccr.2012.09.021 |
| PUBMED: | 23153536 |
| PROVIDER: | scopus |
| PMCID: | PMC3510660 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 26 March 2013" - "CODEN: CCAEC" - "Source: Scopus" |
