ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth

EMBO J. 2005 Oct 5;24(19):3470-81. doi: 10.1038/sj.emboj.7600777. Epub 2005 Sep 8.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Cell Line, Tumor
  • Cell Survival / genetics
  • Cell Survival / physiology
  • Endoplasmic Reticulum / physiology*
  • Eukaryotic Initiation Factor-2 / metabolism*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Hypoxia / physiopathology*
  • Immunohistochemistry
  • Mice
  • Mice, Nude
  • Mutation / genetics
  • Neoplasms / metabolism
  • Neoplasms / physiopathology*
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Stress, Physiological / metabolism
  • Stress, Physiological / physiopathology*
  • Transcription Factor CHOP / metabolism
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism*


  • ATF4 protein, human
  • DDIT3 protein, human
  • Eukaryotic Initiation Factor-2
  • Activating Transcription Factor 4
  • Transcription Factor CHOP
  • PERK kinase
  • eIF-2 Kinase