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ER Stress, Hypoxia Tolerance and Tumor Progression
Abstract
The development of chronic and fluctuating hypoxic regions in tumors has profound consequences for malignant progression, response to therapy and overall patient survival. Understanding the events involved in hypoxia tolerance will offer new opportunities for antitumor modalities. A universal response of tumor cells to hypoxia is a rapid and substantial decrease in the rates of macromolecular synthesis. Hypoxia induces phosphorylation of the translation initiation factor eIF2alpha on Ser51 via activation of the endoplasmic reticulum (ER) resident kinase PERK and that this modification is required for the rapid downregulation of global protein synthesis by this hypoxic stress. PERK-dependent phosphorylation of eIF2alpha is one component of the Unfolded Protein Response (UPR), a coordinated program that promotes cell survival under conditions of ER stress. Inactivation of PERK or eIF2alpha phosphorylation impairs cell survival under hypoxia, and transformed cells with inactivating PERK or eIF2alpha mutations form tumors in nude mice that are slower growing, and have higher levels of apoptosis in hypoxic areas compared to tumors with an intact UPR. Expression of the transcription factor ATF4, a downstream effector of eIF2alpha phosphorylation, is also upregulated by hypoxia in vitro and in human tumors and increases hypoxia tolerance. A second UPR pathway mediated by activation of IRE1 and its downstream target XBP1 is also required for hypoxia tolerance in vitro and for tumor growth. These results reveal a critical role for UPR activation for tumor cell resistance to hypoxia and tumor growth promotion and suggest that the UPR may be an attractive target for anti-tumor modalities.
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“Folding capacity may therefore be compromised if oxygen or ATP concentrations are limiting, but this is likely to be a secondary mechanism (315).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [315]
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The Role of Endoplasmic Reticulum Stress in Human Pathology
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Endoplasmic reticulum stress signals in the tumour and its microenvironment
Chen, X., & Cubillos-Ruiz, J. R. (2021) · Nature Reviews Cancer · doi:10.1038/s41568-020-00312-2 · Cited by 1,356
Pesticides and human chronic diseases: Evidences, mechanisms, and perspectives
Mostafalou, S., & Abdollahi, M. R. (2013) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2013.01.025 · Cited by 1,333
“, 2010), tumor formation and progression (Koumenis, 2006; Lee and Hendershot, 2006), atherosclerosis, cardiomyopathy, chronic kidney diseases and renal failure (Dickhout et al.”
BackgroundRozpędek‐Kamińska, W., Pytel, D., Mucha, B., Leszczynska, H., Diehl, J. A., & Majsterek, I. (2016) · Current Molecular Medicine · doi:10.2174/1566524016666160523143937 · Cited by 894
“The significant ATP reduction that is due to oxygen and energy deprivation is strictly affiliated with a rapid decrease in the rate of protein translation that is crucial for the adaptation of tumor cells to survive in the adverse conditions [32].”
BackgroundInfluentialThe eIF2α kinases: their structures and functions
Donnelly, N., Gorman, A. M., Gupta, S., & Samali, A. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1252-6 · Cited by 906
“Hypoxia is a potent inducer of PERK-dependent eIF2α phosphorylation and in line with PERK’s important prosurvival function in cells exposed to hypoxia, PERK signaling can increase tumor size, vascularization, and rates of cell survival (reviewed in [102]).”
Metadata
- Authors
- Koumenis, C.
- Affiliations
- Wake Forest University Health Sciences (US)
- Corresponding author
- Koumenis, Constantinos
- Venue
- Current Molecular Medicine
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2006-02-01
- Volume
- 6
- Issue
- 1
- Pages
- 55-69
- ISSN
- 1566-5240 (ISSN-L)
- OpenAlex
- W2000859982
- Cited by
- 231
- References
- 0
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 7 · 2023: 11 · 2022: 6 · 2021: 4 · 2020: 12 · 2019: 8 · 2018: 7 · 2017: 8 · 2016: 14 · 2015: 20 · 2014: 19 · 2013: 16 · 2012: 15
- FWCI
- 7.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01 CA94214, R01CA094214)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- endoplasmic reticulum stress, hypoxia tolerance, tumor progression, unfolded protein response, PERK, eIF2α phosphorylation, ATF4, IRE1, XBP1, tumor hypoxia, apoptosis
- MeSH terms
- Animals, Endoplasmic Reticulum, Humans, Neoplasms, Cell Hypoxia, Protein Folding, Disease Progression, eIF-2 Kinase
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