期刊
CARCINOGENESIS
卷 28, 期 1, 页码 215-222出版社
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgl139
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资金
- NATIONAL CANCER INSTITUTE [P30CA023074, R01CA119087, R21CA111513, P01CA072008, P50CA095060] Funding Source: NIH RePORTER
- NCI NIH HHS [1 P50CA95060-01, 1R01CA119087-01A1, 1R21CA111513-01A1, CA23074, CA72008] Funding Source: Medline
Nuclear factor kappa B (NF-kappa B) is a redox-associated transcription factor that is involved in the activation of survival pathways. We have previously shown that deoxycholate (DOC) activates NF-kappa B 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-kappa B, which is associated with the development of apoptosis resistance. The mechanisms by which DOC activates NF-kappa B in colon epithelial cells, and whether natural antioxidants can reduce DOC-induced NF-kappa B 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-kappa B activation. Since we have previously shown that DOC activates the NF-kappa B stress-response pathway in HCT-116 cells, we used this cell line to further explore the mechanisms of NF-kappa B activation. We found that DOC induces mitochondrial oxidative stress and activates NF-kappa B 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-kappa B activation was significantly (P < 0.05) inhibited by pre-treatment of cells with CAPE, EGCG, TMS, DPI, NaN3, EGTA, Ouabain and RuR. The NF-kappa B-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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