Deoxycholate induces mitochondrial oxidative stress and activates NF- B through multiple mechanisms in HCT-116 colon epithelial cells
Abstract
Nuclear factor kappa B (NF-kappaB) is a redox-associated transcription factor that is involved in the activation of survival pathways. We have previously shown that deoxycholate (DOC) activates NF-kappaB in hepatocytes and colon epithelial cells and that persistent exposure of HCT-116 cells to increasing concentrations of DOC results in the constitutive activation of NF-kappaB, which is associated with the development of apoptosis resistance. The mechanisms by which DOC activates NF-kappaB in colon epithelial cells, and whether natural antioxidants can reduce DOC-induced NF-kappaB activation, however, are not known. Also, it is not known if DOC can generate reactive oxygen species within mitochondria as a possible pathway of stress-related NF-kappaB activation. Since we have previously shown that DOC activates the NF-kappaB stress-response pathway in HCT-116 cells, we used this cell line to further explore the mechanisms of NF-kappaB activation. We found that DOC induces mitochondrial oxidative stress and activates NF-kappaB in HCT-116 cells through multiple mechanisms involving NAD(P)H oxidase, Na+/K+-ATPase, cytochrome P450, Ca++ and the terminal mitochondrial respiratory complex IV. DOC-induced NF-kappaB activation was significantly (P < 0.05) inhibited by pre-treatment of cells with CAPE, EGCG, TMS, DPI, NaN3, EGTA, Ouabain and RuR. The NF-kappaB-activating pathways, induced by the dietary-related endogenous detergent DOC, provide mechanisms for promotion of colon cancer and identify possible new targets for chemoprevention.
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Obesity-associated alterations in gut microbiota can lead to increased levels of the genotoxic metabolite DCA, a secondary bile acid known to cause DNA damage.
“We previously demonstrated that obesityassociated alterations in gut microbiota can lead to increased levels of the genotoxic metabolite deoxycholic acid (DCA), a secondary bile acid known to cause DNA damage [47].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [47]
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Bile acids as endogenous etiologic agents in gastrointestinal cancer
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XPD localizes in mitochondria and protects the mitochondrial genome from oxidative DNA damage
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- Authors
- Payne, C. M., Weber, C., Crowley-Skillicorn, C., Dvorak, K., Bernstein, H., Bernstein, C., Holubec, H., Dvorakova, B., & Garewal, H.
- Affiliations
- University of Arizona (US)
- Corresponding author
- Payne, C.M.
- Venue
- Carcinogenesis
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-01-01
- Volume
- 28
- Issue
- 1
- Pages
- 215-222
- ISSN
- 0143-3334 (ISSN-L)
- 1460-2180
- OpenAlex
- W2101754426
- Cited by
- 166
- References
- 100
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 10 · 2023: 12 · 2022: 9 · 2021: 15 · 2020: 8 · 2019: 7 · 2018: 9 · 2017: 9 · 2016: 5 · 2015: 9 · 2014: 9 · 2013: 3 · 2012: 7
- FWCI
- 2.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Carcinogenesis (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r21ca111513-02, CA 23074)
- National Cancer Institute (CA 72008, CA 23074, 1P50CA95060-01, R01CA119087, 1R21CA111513-01A1, P01CA072008, P50CA095060, P30CA023074)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- deoxycholate, NF-κB activation, mitochondrial oxidative stress, HCT116 cells, colonic epithelial cells, NADPH oxidase, Na+/K+-ATPase, cytochrome P450, calcium signaling, reactive oxygen species, apoptosis resistance, colon cancer chemoprevention, dietary bile acids, antioxidants
- MeSH terms
- Sodium-Potassium-Exchanging ATPase, Antioxidants, Calcium, Electron Transport Complex IV, Cytochrome P-450 Enzyme System, Deoxycholic Acid, Detergents, Humans, Oxidation-Reduction, NF-kappa B, Reactive Oxygen Species, Oxidative Stress, NADPH Oxidases, HCT116 Cells, Membrane Potential, Mitochondrial
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