Cited by 231Endoplasmic Reticulum Stress and DiseaseCancer, Hypoxia, and MetabolismCell death mechanisms and regulation

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ER Stress, Hypoxia Tolerance and Tumor Progression

Koumenis, Constantinos·2006·Current Molecular Medicine

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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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Hypoxic regulation of MYBL1, MEST, TCF3, TCF8, GTF2B, GTF2F2 and SNAI2 genes expression in U87 glioma cells upon IRE1 inhibition
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Background
Are cachexia-associated tumors transmitTERS of ER stress?
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Background
Interferon γ suppresses dentin sialophosphoprotein in oral squamous cell carcinoma cells resulting in antitumor effects, via modulation of the endoplasmic reticulum response
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Prognostic Role of Unfolded Protein Response-Related Genes in Hepatocellular Carcinoma
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Authors: Koumenis, C.
Affiliations: Wake Forest University Health Sciences (US)
Corresponding author: Koumenis, Constantinos
ORCID: 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)
DOI: 10.2174/156652406775574604
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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ER Stress, Hypoxia Tolerance and Tumor Progression

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