The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation.
The transcription factor ATF4 regulates the expression of genes involved in amino acid metabolism, redox homeostasis and ER stress responses, and it is overexpressed in human solid tumours, suggesting that it has an important function in tumour progression. Here, we report that inhibition of ATF4 expression blocked proliferation and survival of transformed cells, despite an initial activation of cytoprotective macroautophagy. Knockdown of ATF4 significantly reduced the levels of asparagine synthetase (ASNS) and overexpression of ASNS or supplementation of asparagine in trans, reversed the proliferation block and increased survival in ATF4 knockdown cells. Both amino acid and glucose deprivation, stresses found in solid tumours, activated the upstream eukaryotic initiation factor 2alpha (eIF2alpha) kinase GCN2 to upregulate ATF4 target genes involved in amino acid synthesis and transport. GCN2 activation/overexpression and increased phospho-eIF2alpha were observed in human and mouse tumours compared with normal tissues and abrogation of ATF4 or GCN2 expression significantly inhibited tumour growth in vivo. We conclude that the GCN2-eIF2alpha-ATF4 pathway is critical for maintaining metabolic homeostasis in tumour cells, making it a novel and attractive target for anti-tumour approaches.
Ye
Jiangbin
J
Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Kumanova
Monika
M
Hart
Lori S
LS
Sloane
Kelly
K
Zhang
Haiyan
H
De Panis
Diego N
DN
Bobrovnikova-Marjon
Ekaterina
E
Diehl
J Alan
JA
Ron
David
D
Koumenis
Constantinos
C
D051701:Activating Transcription Factor 4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D003470:Culture Media / Q000737:chemistry; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D006801:Humans; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*
C497109:ATF4 protein, human; D000596:Amino Acids; C081452:Atf4 protein, mouse; D003470:Culture Media; D051701:Activating Transcription Factor 4; C529271:EIF2AK4 protein, human; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D005947:Glucose
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