title: ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth.
abstract: Tumor cell adaptation to hypoxic stress is an important determinant of malignant progression. While much emphasis has been placed on the role of HIF-1 in this context, the role of additional mechanisms has not been adequately explored. Here we demonstrate that cells cultured under hypoxic/anoxic conditions and transformed cells in hypoxic areas of tumors activate a translational control program known as the integrated stress response (ISR), which adapts cells to endoplasmic reticulum (ER) stress. Inactivation of ISR signaling by mutations in the ER kinase PERK and the translation initiation factor eIF2alpha or by a dominant-negative PERK impairs cell survival under extreme hypoxia. Tumors derived from these mutant cell lines are smaller and exhibit higher levels of apoptosis in hypoxic areas compared to tumors with an intact ISR. Moreover, expression of the ISR targets ATF4 and CHOP was noted in hypoxic areas of human tumor biopsy samples. Collectively, these findings demonstrate that activation of the ISR is required for tumor cell adaptation to hypoxia, and suggest that this pathway is an attractive target for antitumor modalities.
authors.affiliation: Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Meixia
authors.initials: M
authors.lastname: Bi
authors.forename: Christine
authors.initials: C
authors.lastname: Naczki
authors.forename: Marianne
authors.initials: M
authors.lastname: Koritzinsky
authors.forename: Diane
authors.initials: D
authors.lastname: Fels
authors.forename: Jaime
authors.initials: J
authors.lastname: Blais
authors.forename: Nianping
authors.initials: N
authors.lastname: Hu
authors.forename: Heather
authors.initials: H
authors.lastname: Harding
authors.forename: Isabelle
authors.initials: I
authors.lastname: Novoa
authors.forename: Mahesh
authors.initials: M
authors.lastname: Varia
authors.forename: James
authors.initials: J
authors.lastname: Raleigh
authors.forename: Donalyn
authors.initials: D
authors.lastname: Scheuner
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.forename: John
authors.initials: J
authors.lastname: Bell
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.forename: Bradly G
authors.initials: BG
authors.lastname: Wouters
authors.forename: Constantinos
authors.initials: C
authors.lastname: Koumenis
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000502:physiology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013312:Stress, Physiological / Q000378:metabolism / Q000503:physiopathology*; D051742:Transcription Factor CHOP / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D051701:Activating Transcription Factor 4; D015852:Eukaryotic Initiation Factor-2; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C497109:ATF4 protein, human; C497249:DDIT3 protein, human