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ER stress‐regulated translation increases tolerance to extreme hypoxia and promotes tumor growth
Author(s) -
Bi Meixia,
Naczki Christine,
Koritzinsky Marianne,
Fels Diane,
Blais Jaime,
Hu Nianping,
Harding Heather,
Novoa Isabelle,
Varia Mahesh,
Raleigh James,
Scheuner Donalyn,
Kaufman Randal J,
Bell John,
Ron David,
Wouters Bradly G,
Koumenis Constantinos
Publication year - 2005
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600777
Subject(s) - biology , atf4 , unfolded protein response , hypoxia (environmental) , integrated stress response , cancer research , microbiology and biotechnology , signal transduction , chop , apoptosis , cellular adaptation , translation (biology) , endoplasmic reticulum , genetics , gene , messenger rna , chemistry , organic chemistry , oxygen
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 eIF2α 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.