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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Background
Taxol-induced unfolded protein response activation in breast cancer cells exposed to hypoxia: ATF4 activation regulates autophagy and inhibits apoptosis
Notte, A., Rebucci, M., Fransolet, M., Roegiers, E., Genin, M., Tellier, C., Watillon, K., Fattaccioli, A., Arnould, T., & Michiels, C. (2015) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2015.02.010 · Cited by 65
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“Several studies indeed suggested that ion channels constitute one of the main client protein families for S1R (Carnally et al., 2010; Crottès et al., 2011; Balasuriya et al., 2012; Kourrich et al., 2012).”
Background
MicroRNA 107 Partly Inhibits Endothelial Progenitor Cells Differentiation via HIF-1β
Meng, S., Cao, J., Wang, L., Zhou, Q., Li, Y., Shen, C., Zhang, X., & Wang, C. (2012) · PLoS ONE · doi:10.1371/journal.pone.0040323 · Cited by 60
“Contrarily, other researchers have reported that the 39UTR of HIF-1b contained a potential binding element for miR-107 with an 8-nt match to the miR-107 seed region, suggesting that the HIF-1b 39UTR is a target of miR-107 [21].”
Background
Severe Burn-Induced Endoplasmic Reticulum Stress and Hepatic Damage in Mice
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“The UPR is clinically important in cancer, diabetic mellitus, and human genetic diseases (11-13).”
Background
Drosophila Genome-Wide RNAi Screen Identifies Multiple Regulators of HIF–Dependent Transcription in Hypoxia
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“As a result, ATF4 induces the expression of genes in response to hypoxia, but remarkably, this response is HIF-independent [19,38].”
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“HIF regulates the expression of >60 genes involved in angiogenesis, anaerobic glycolysis and cell survival, and the coordinated expression of these genes results in cellular adaptation to acute and chronic hypoxia (81).”
Endothelial damage and stem cell repair in atherosclerosis
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Influential
Inhibitors of Advanced Glycation and Endoplasmic Reticulum Stress
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“Hypoxia-induced mutations or upregulation of key regulator genes can select tumor cells with an increased resistance to treatment and drive the tumor towards a more malignant phenotype [38,49–51].”
Background
Inhibition of Mesothelin as a Novel Strategy for Targeting Cancer Cells
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MicroRNA-103/107 is involved in hypoxia-induced proliferation of pulmonary arterial smooth muscle cells by targeting HIF-1β
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Activating CCT2 triggers Gli-1 activation during hypoxic condition in colorectal cancer
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Adipose tissue dysfunction and its effects on tumor metabolism
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“It was also shown that activating transcription factor 4 (ATF4), an ER stress response protein, has the ability to bind to HREs and HIF-1α target genes such as VEGF, potentiating HIF-1α activity under stress conditions [238, 239].”
Background
New Castanospermine Glycoside Analogues Inhibit Breast Cancer Cell Proliferation and Induce Apoptosis without Affecting Normal Cells
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“Given that ER stress-mediated activation of the UPR occurs in cancer tissues and cell lines [64,65,66], we can hypothesized that the observed effects of the CS-related sp(2)-iminosugar glycosides in BC cells cycle, that is the blockade at G1 in MCF7 and at G2/M in MDA-MB-231 cells by CO-OCS and at G2/M in either of th…”
Background
Overexpression of X-Box Binding Protein 1 (XBP1) Correlates to Poor Prognosis and Up-Regulation of PI3K/mTOR in Human Osteosarcoma
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Rhinovirus and Innate Immune Function of Airway Epithelium
Ganjian, H., Rajput, C., Elzoheiry, M., & Sajjan, U. S. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00277 · Cited by 45
“Furthermore, pathophysiological stress signals such as viral infection, accumulation of misfolded proteins, hypoxia ER-Ca2 depletion can cause ER stress (Kaufman, 1999; Koumenis, 2006; Jheng et al., 2010; Song et al., 2019).”
Background
A systems toxicology approach on the mechanism of uptake and toxicity of MWCNT in Caenorhabditis elegans
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The Role of the Hypoxia-Related Unfolded Protein Response (UPR) in the Tumor Microenvironment
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Unfolded Protein Response as a Therapeutic Target in Cardiovascular Disease
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Endoplasmic Reticulum Stress Signaling Pathways: Activation and Diseases
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Endoplasmic Reticulum Stress in Disease Pathogenesis
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An RNA Interference Screen Identifies a Novel Regulator of Target of Rapamycin That Mediates Hypoxia Suppression of Translation inDrosophilaS2 Cells
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“Among them, hypoxia-induced inhibition of protein translation has been studied in detail (Liu and Simon, 2004; Wouters et al., 2005; Koumenis, 2006; Koumenis and Maxwell, 2006; Liu et al., 2006).”
Background
Chronic hypoxia and Cu2+ exposure induce gill remodeling of largemouth bass through endoplasmic reticulum stress, mitochondrial damage and apoptosis
Liu, Q., Wang, H., Ge, J., Li, L., Luo, J., He, K., Yan, H., Zhang, X., Tahir, R., Luo, W., et al. (2022) · Aquatic Toxicology · doi:10.1016/j.aquatox.2022.106373 · Cited by 41

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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