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Direct Transcriptional Up-regulation of Cyclooxygenase-2 by Hypoxia-Inducible Factor (HIF)-1 Promotes Colorectal Tumor Cell Survival and Enhances HIF-1 Transcriptional Activity during Hypoxia
Abstract
Cyclooxygenase (COX)-2, the inducible key enzyme for prostanoid biosynthesis, is overexpressed in most colorectal carcinomas and a subset of colorectal adenomas. Genetic, biochemical, and clinical evidence indicates an important role for COX-2 in colorectal tumorigenesis. Although COX-2 can be induced by aberrant growth factor signaling and oncogene activation during colorectal tumorigenesis, the role of microenvironmental factors such as hypoxia in COX-2 regulation remains to be elucidated. For the first time, we report that under hypoxic conditions COX-2 protein levels increase in colorectal adenoma and carcinoma cells. Rigorous analyses reveal that COX-2 up-regulation is transcriptional and is associated with hypoxia-inducible factor (HIF)-1alpha induction. Oligonucleotide pull-down and chromatin immunoprecipitation assays reveal that HIF-1alpha binds a hypoxia-responsive element on the COX-2 promoter. COX-2 up-regulation during hypoxia is accompanied by increased levels of prostaglandin E(2) (PGE(2)), which promote tumor cell survival under hypoxic conditions. In addition, elevated levels of PGE(2) in hypoxic colorectal tumor cells enhance vascular endothelial growth factor expression and HIF-1 transcriptional activity by activating the mitogen-activated protein kinase pathway, showing a potential positive feedback loop that contributes to COX-2 up-regulation during hypoxia. This study identifies COX-2 as a direct target for HIF-1 in colorectal tumor cells. In addition, COX-2 up-regulation represents a pivotal cellular adaptive response to hypoxia with implication for colorectal tumor cell survival and angiogenesis. We propose that using modified COX-2-selective inhibitors, which are only activated under hypoxic conditions, could potentially be a novel more selective strategy for colorectal cancer prevention and treatment.
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“In addition, hypoxia also induces COX-2 [86].”
From The Pathogenesis of Adenomyosis vis-à-vis Endometriosis (2020) · cites this paper as [86]
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Metadata
- Authors
- Kaidi, A., Qualtrough, D., Williams, A. C., & Paraskeva, C.
- Affiliations
- Cancer Research UK (GB)
- Venue
- Cancer Research
- Published
- 2006-07-01
- Volume
- 66
- Issue
- 13
- Pages
- 6683-6691
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2008854828
- Cited by
- 300
- References
- 49
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 10 · 2023: 6 · 2022: 13 · 2021: 17 · 2020: 24 · 2019: 18 · 2018: 13 · 2017: 16 · 2016: 17 · 2015: 23 · 2014: 16 · 2013: 19 · 2012: 22
- FWCI
- 7.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion)
- Explore Bristol Research (submittedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Inflammatory mediators and NSAID effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- cyclooxygenase-2, hypoxia-inducible factor-1α, colorectal cancer, colorectal adenoma, hypoxia, prostaglandin E2, hypoxia response element, transcriptional regulation, vascular endothelial growth factor, MAPK signaling, tumor cell survival, angiogenesis, COX-2 selective inhibitors, tumor microenvironment
- MeSH terms
- Base Sequence, Cell Survival, Humans, Molecular Sequence Data, Promoter Regions, Genetic, Transcription, Genetic, Colorectal Neoplasms, Dinoprostone, Cell Hypoxia, Up-Regulation, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, HT29 Cells, MAP Kinase Signaling System, HCT116 Cells, Cell Growth Processes, Cyclooxygenase 2, Hypoxia-Inducible Factor 1, alpha Subunit
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