Article
- The EMBO Journal (2005) 24, 3470 - 3481
- doi:10.1038/sj.emboj.7600777
Published online: 8 September 2005
Subject Categories:
ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth
Meixia Bi1, Christine Naczki1, Marianne Koritzinsky2, Diane Fels1,3, Jaime Blais4, Nianping Hu1, Heather Harding5, Isabelle Novoa5, Mahesh Varia6, James Raleigh6, Donalyn Scheuner7, Randal J Kaufman7, John Bell4, David Ron5, Bradly G Wouters2 and Constantinos Koumenis1,3,8
- Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- Department of Radiation Oncology, GROW Research Institute, University of Maastricht, Maastricht, The Netherlands
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- Ottawa Regional Cancer Center, Ontario, Canada
- Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY, USA
- Department of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, NC, USA
- Howard Hughes Medical Institute and Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI, USA
- Department of Neurosurgery, Wake Forest University School of Medicine, Winston-Salem, NC, USA
Correspondence to:
Constantinos Koumenis, Departments of Radiation Oncology, Cancer Biology and Neurosurgery, NRC, Room 411, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA. Tel.: +1 336 713 7637; Fax: +1 336 713 7639; E-mail: ckoumeni@wfubmc.edu
Received 24 March 2005; Accepted 19 July 2005
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 eIF2
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.
Keywords:
- apoptosis,
- ATF4,
- endoplasmic reticulum,
- hypoxia,
- PERK
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The EMBO Journal Article (08 Mar 2006)
