title: ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth.
abstract: The proto-oncogene c-Myc paradoxically activates both proliferation and apoptosis. In the pathogenic state, c-Myc-induced apoptosis is bypassed via a critical, yet poorly understood escape mechanism that promotes cellular transformation and tumorigenesis. The accumulation of unfolded proteins in the ER initiates a cellular stress program termed the unfolded protein response (UPR) to support cell survival. Analysis of spontaneous mouse and human lymphomas demonstrated significantly higher levels of UPR activation compared with normal tissues. Using multiple genetic models, we demonstrated that c-Myc and N-Myc activated the PERK/eIF2α/ATF4 arm of the UPR, leading to increased cell survival via the induction of cytoprotective autophagy. Inhibition of PERK significantly reduced Myc-induced autophagy, colony formation, and tumor formation. Moreover, pharmacologic or genetic inhibition of autophagy resulted in increased Myc-dependent apoptosis. Mechanistically, we demonstrated an important link between Myc-dependent increases in protein synthesis and UPR activation. Specifically, by employing a mouse minute (L24+/-) mutant, which resulted in wild-type levels of protein synthesis and attenuation of Myc-induced lymphomagenesis, we showed that Myc-induced UPR activation was reversed. Our findings establish a role for UPR as an enhancer of c-Myc-induced transformation and suggest that UPR inhibition may be particularly effective against malignancies characterized by c-Myc overexpression.
authors.affiliation: Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-5156, USA.
authors.forename: Lori S
authors.initials: LS
authors.lastname: Hart
authors.forename: John T
authors.initials: JT
authors.lastname: Cunningham
authors.forename: Tatini
authors.initials: T
authors.lastname: Datta
authors.forename: Souvik
authors.initials: S
authors.lastname: Dey
authors.forename: Feven
authors.initials: F
authors.lastname: Tameire
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Lehman
authors.forename: Bo
authors.initials: B
authors.lastname: Qiu
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhang
authors.forename: George
authors.initials: G
authors.lastname: Cerniglia
authors.forename: Meixia
authors.initials: M
authors.lastname: Bi
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.forename: Huayi
authors.initials: H
authors.lastname: Liu
authors.forename: Changhong
authors.initials: C
authors.lastname: Li
authors.forename: Amit
authors.initials: A
authors.lastname: Maity
authors.forename: Andrei
authors.initials: A
authors.lastname: Thomas-Tikhonenko
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Perl
authors.forename: Albert
authors.initials: A
authors.lastname: Koong
authors.forename: Serge Y
authors.initials: SY
authors.lastname: Fuchs
authors.forename: J Alan
authors.initials: JA
authors.lastname: Diehl
authors.forename: Ian G
authors.initials: IG
authors.lastname: Mills
authors.forename: Davide
authors.initials: D
authors.lastname: Ruggero
authors.forename: Constantinos
authors.initials: C
authors.lastname: Koumenis
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D002051:Burkitt Lymphoma / Q000378:metabolism* / Q000473:pathology; D020013:Calcium Signaling; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D016000:Cluster Analysis; D059865:Endoplasmic Reticulum Stress; D055786:Gene Knockout Techniques; D006579:Heterozygote; D006801:Humans; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism / Q000502:physiology*; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D020169:Caspases; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D012269:Ribosomal Proteins; D019892:eIF-2 Kinase; C000715470:MAS1 protein, human; C489427:MYC protein, human; C036298:ribosomal protein L24