title: The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Jiangbin
authors.initials: J
authors.lastname: Ye
authors.forename: Monika
authors.initials: M
authors.lastname: Kumanova
authors.forename: Lori S
authors.initials: LS
authors.lastname: Hart
authors.forename: Kelly
authors.initials: K
authors.lastname: Sloane
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhang
authors.forename: Diego N
authors.initials: DN
authors.lastname: De Panis
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Bobrovnikova-Marjon
authors.forename: J Alan
authors.initials: JA
authors.lastname: Diehl
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.forename: Constantinos
authors.initials: C
authors.lastname: Koumenis
mesh_terms: 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*
chemical_list: 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
references.citation: Mol Cell Biol. 2002 Oct;22(19):6681-8
references.pmid: 12215525
references.citation: Curr Biol. 2002 Aug 6;12(15):1279-86
references.pmid: 12176355
references.citation: Cancer Res. 2000 Sep 15;60(18):5027-30
references.pmid: 11016623
references.citation: J Biol Chem. 2004 Dec 24;279(52):53937-46
references.pmid: 15475356
references.citation: Proc Natl Acad Sci U S A. 1984 Oct;81(20):6442-6
references.pmid: 6387704
references.citation: Mol Cancer Ther. 2008 Oct;7(10):3123-8
references.pmid: 18852115
references.citation: Am J Physiol. 1997 May;272(5 Pt 1):C1691-9
references.pmid: 9176161
references.citation: Mol Pharmacol. 2008 May;73(5):1491-501
references.pmid: 18252805
references.citation: Cancer Res. 1979 Oct;39(10):3893-6
references.pmid: 383278
references.citation: Nature. 2005 Aug 25;436(7054):1166-73
references.pmid: 16121183
references.citation: J Biol Chem. 1979 Apr 25;254(8):2669-76
references.pmid: 429309
references.citation: J Biol Chem. 2004 Aug 27;279(35):36553-61
references.pmid: 15213227
references.citation: Cancer Res. 2009 May 15;69(10):4415-23
references.pmid: 19417138
references.citation: Biochem J. 2008 Mar 15;410(3):485-93
references.pmid: 18052927
references.citation: Cell. 2004 Apr 30;117(3):387-98
references.pmid: 15109498
references.citation: Cell. 1986 Apr 25;45(2):201-7
references.pmid: 3516411
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19345-50
references.pmid: 18032601
references.citation: Cell Metab. 2008 Jan;7(1):11-20
references.pmid: 18177721
references.citation: J Cell Biol. 2004 Oct 11;167(1):27-33
references.pmid: 15479734
references.citation: Oncogene. 2007 Jul 19;26(33):4749-60
references.pmid: 17297441
references.citation: Mol Cell. 2003 Mar;11(3):619-33
references.pmid: 12667446
references.citation: Cell Metab. 2005 Apr;1(4):273-7
references.pmid: 16054071
references.citation: Biochem J. 2005 Jan 15;385(Pt 2):371-80
references.pmid: 15355306
references.citation: Mol Biol Cell. 2005 Dec;16(12):5493-501
references.pmid: 16176978
references.citation: Mol Cell Biol. 2002 Nov;22(21):7405-16
references.pmid: 12370288
references.citation: Cancer Res. 1982 Oct;42(10):4090-7
references.pmid: 7105007
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11269-74
references.pmid: 15277680
references.citation: Mol Cell Biol. 2000 Apr;20(8):2706-17
references.pmid: 10733573
references.citation: Autophagy. 2008 Feb;4(2):151-75
references.pmid: 18188003
references.citation: Cell Metab. 2007 Feb;5(2):103-14
references.pmid: 17276353
references.citation: Biochem J. 2001 Jul 1;357(Pt 1):321-8
references.pmid: 11415466
references.citation: Mol Cell. 2000 Nov;6(5):1099-108
references.pmid: 11106749
references.citation: Mol Cell Biol. 1992 Dec;12(12):5801-15
references.pmid: 1448107
references.citation: Mol Cell Biol. 1995 Aug;15(8):4497-506
references.pmid: 7623840
references.citation: Biochem J. 2004 Apr 1;379(Pt 1):79-88
references.pmid: 14715082
references.citation: Cancer Res. 2007 Apr 1;67(7):3345-55
references.pmid: 17409444
references.citation: Nucleic Acids Res. 1990 Jun 25;18(12):3509-13
references.pmid: 1972978
references.citation: Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):190-5
references.pmid: 11756670
references.citation: Annu Rev Pharmacol. 1970;10:421-40
references.pmid: 4911021
references.citation: Science. 2005 Mar 18;307(5716):1776-8
references.pmid: 15774759
references.citation: Biochem J. 2009 Feb 1;417(3):695-703
references.pmid: 18840095
references.citation: Genes Cells. 1998 Dec;3(12):801-10
references.pmid: 10096021
references.citation: Blood. 2004 Mar 1;103(5):1876-82
references.pmid: 14604972
references.citation: Mol Cell Biol. 1990 Jun;10(6):2820-31
references.pmid: 2188100
references.citation: Cancer Res. 1996 May 15;56(10):2250-5
references.pmid: 8625293
references.citation: Proc Natl Acad Sci U S A. 1987 Mar;84(6):1565-9
references.pmid: 3470743
references.citation: Blood. 2002 Feb 1;99(3):736-45
references.pmid: 11806972
references.citation: J Biol Chem. 2002 Jul 5;277(27):24120-7
references.pmid: 11960987
references.citation: J Cell Biochem. 2008 Oct 15;105(3):885-95
references.pmid: 18729081
references.citation: EMBO J. 2005 Oct 5;24(19):3470-81
references.pmid: 16148948
references.citation: Annu Rev Biochem. 2006;75:629-54
references.pmid: 16756505
references.citation: PLoS One. 2009 Nov 24;4(11):e8008
references.pmid: 19956728
references.citation: Adv Enzymol Relat Areas Mol Biol. 1998;72:145-98
references.pmid: 9559053