Deoxycholate induces mitochondrial oxidative stress and activates NF-kappaB through multiple mechanisms in HCT-116 colon epithelial cells.
Carcinogenesis
; 28(1): 215-22, 2007 Jan.
Article
en En
| MEDLINE
| ID: mdl-16887864
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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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
FN-kappa B
/
Estrés Oxidativo
/
Ácido Desoxicólico
/
Detergentes
/
Potencial de la Membrana Mitocondrial
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Carcinogenesis
Año:
2007
Tipo del documento:
Article
País de afiliación:
Estados Unidos