Cited by 166NF-κB Signaling PathwaysGenomics, phytochemicals, and oxidative stressBioactive Compounds and Antitumor Agents

Deoxycholate induces mitochondrial oxidative stress and activates NF- B through multiple mechanisms in HCT-116 colon epithelial cells

Payne, C.M., Weber, C., Crowley-Skillicorn, C., Dvorak, K., Bernstein, H., Bernstein, C., Holubec, H., Dvorakova, B. +1 more·2007·Carcinogenesis

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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Crossref · 10.1093/carcin/bgl139

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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].”

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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
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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