title: Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors.
abstract: Autophagic elimination of defective mitochondria suppresses oxidative stress and preserves mitochondrial function. Here, the essential autophagy gene Atg7 was deleted in a mouse model of BrafV600E-induced lung cancer in the presence or absence of the tumor suppressor Trp53. Atg7 deletion initially induced oxidative stress and accelerated tumor cell proliferation in a manner indistinguishable from Nrf2 ablation. Compound deletion of Atg7 and Nrf2 had no additive effect, suggesting that both genes modulate tumorigenesis by regulating oxidative stress and revealing a potential mechanism of autophagy-mediated tumor suppression. At later stages of tumorigenesis, Atg7 deficiency resulted in an accumulation of defective mitochondria, proliferative defects, reduced tumor burden, conversion of adenomas and adenocarcinomas to oncocytomas, and increased mouse life span. Autophagy-defective tumor-derived cell lines were impaired in their ability to respire and survive starvation and were glutamine-dependent, suggesting that autophagy-supplied substrates from protein degradation sustains BrafV600E tumor growth and metabolism.
  
  
  CONCLUSIONS
  The essential autophagy gene Atg7 functions to promote BrafV600E-driven lung tumorigenesis by preserving mitochondrial glutamine metabolism. This suggests that inhibiting autophagy is a novel approach to treating BrafV600E-driven cancers.
authors: 1Cancer Institute of New Jersey, New Brunswick; 2Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey; and 3Department of Cellular & Molecular Pharmacology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors: Anne M
authors: AM
authors: Strohecker
authors: Jessie Yanxiang
authors: JY
authors: Guo
authors: Gizem
authors: G
authors: Karsli-Uzunbas
authors: Sandy M
authors: SM
authors: Price
authors: Guanghua Jim
authors: GJ
authors: Chen
authors: Robin
authors: R
authors: Mathew
authors: Martin
authors: M
authors: McMahon
authors: Eileen
authors: E
authors: White
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D000236:Adenoma / Q000473:pathology; D018249:Adenoma, Oxyphilic / Q000473:pathology; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004195:Disease Models, Animal; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; D051267:NF-E2-Related Factor 2; D016159:Tumor Suppressor Protein p53; D005973:Glutamine; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D000071193:Autophagy-Related Protein 7
references: FEBS Lett. 1993 Oct 25;333(1-2):169-74
references: 8224160
references: Nat Cell Biol. 2010 Mar;12(3):213-23
references: 20173742
references: Genes Dev. 2007 Jun 1;21(11):1367-81
references: 17510285
references: Cancer Discov. 2013 Aug;3(8):894-907
references: 23650262
references: Genes Dev. 2011 Apr 15;25(8):795-800
references: 21498569
references: Genes Dev. 2011 Jul 15;25(14):1510-27
references: 21764854
references: Genes Dev. 2007 Feb 15;21(4):379-84
references: 17299132
references: Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15077-82
references: 14657337
references: J Hum Genet. 2011 Mar;56(3):230-4
references: 21248763
references: Nat Rev Cancer. 2012 Apr 26;12(6):401-10
references: 22534666
references: EMBO Rep. 2012 Feb 01;13(2):150-6
references: 22222206
references: J Clin Endocrinol Metab. 2004 May;89(5):2414-20
references: 15126572
references: Science. 2010 Dec 3;330(6009):1344-8
references: 21127245
references: J Cell Biol. 2005 May 9;169(3):425-34
references: 15866887
references: Int J Biochem Cell Biol. 2013 Jan;45(1):47-63
references: 22664328
references: Mol Cell Biol. 2004 Aug;24(16):7130-9
references: 15282312
references: Clin Cancer Res. 2011 Feb 15;17(4):654-66
references: 21325294
references: Nature. 2004 Dec 23;432(7020):1032-6
references: 15525940
references: J Clin Invest. 2003 Dec;112(12):1809-20
references: 14638851
references: Genes Dev. 2007 Jul 1;21(13):1621-35
references: 17606641
references: Nat Genet. 2003 Jan;33(1):19-20
references: 12447372
references: Cancer Cell. 2006 Jul;10(1):51-64
references: 16843265
references: Cold Spring Harb Perspect Biol. 2013 Feb 01;5(2):
references: 23378588
references: Nature. 2011 Jul 06;475(7354):106-9
references: 21734707
references: Genes Dev. 2011 Mar 1;25(5):460-70
references: 21317241
references: Mol Biol Cell. 2011 Jan 15;22(2):165-78
references: 21119005
references: Genes Dev. 2013 Jul 1;27(13):1447-61
references: 23824538
references: Nature. 2002 Jun 27;417(6892):949-54
references: 12068308
references: Cancer Cell. 2013 Mar 18;23(3):302-15
references: 23477830
references: J Cell Biol. 2011 Apr 18;193(2):275-84
references: 21482715
references: Nature. 2013 Jun 6;498(7452):109-12
references: 23685455
references: Biochim Biophys Acta. 2011 Jun;1807(6):633-42
references: 20732299
references: Genes Dev. 2011 Apr 1;25(7):717-29
references: 21406549
references: Curr Opin Cell Biol. 2010 Apr;22(2):212-7
references: 20056400
references: Mol Cell Biol. 2010 Jul;30(13):3275-85
references: 20421418
references: Cell. 2009 Jun 12;137(6):1062-75
references: 19524509