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Deoxycholate induces mitochondrial oxidative stress and activates NF-kappaB through multiple mechanisms in HCT-116 colon epithelial cells.
Carcinogenesis. 2007 Jan; 28(1):215-22.C

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.

Authors+Show Affiliations

Department of Cell Biology & Anatomy, College of Medicine, University of Arizona, Tucson, AZ 85724-5044, USA. cpayne@email.arizona.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16887864

Citation

Payne, C M., et al. "Deoxycholate Induces Mitochondrial Oxidative Stress and Activates NF-kappaB Through Multiple Mechanisms in HCT-116 Colon Epithelial Cells." Carcinogenesis, vol. 28, no. 1, 2007, pp. 215-22.
Payne CM, Weber C, Crowley-Skillicorn C, et al. Deoxycholate induces mitochondrial oxidative stress and activates NF-kappaB through multiple mechanisms in HCT-116 colon epithelial cells. Carcinogenesis. 2007;28(1):215-22.
Payne, C. M., Weber, C., Crowley-Skillicorn, C., Dvorak, K., Bernstein, H., Bernstein, C., Holubec, H., Dvorakova, B., & Garewal, H. (2007). Deoxycholate induces mitochondrial oxidative stress and activates NF-kappaB through multiple mechanisms in HCT-116 colon epithelial cells. Carcinogenesis, 28(1), 215-22.
Payne CM, et al. Deoxycholate Induces Mitochondrial Oxidative Stress and Activates NF-kappaB Through Multiple Mechanisms in HCT-116 Colon Epithelial Cells. Carcinogenesis. 2007;28(1):215-22. PubMed PMID: 16887864.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Deoxycholate induces mitochondrial oxidative stress and activates NF-kappaB through multiple mechanisms in HCT-116 colon epithelial cells. AU - Payne,C M, AU - Weber,C, AU - Crowley-Skillicorn,C, AU - Dvorak,K, AU - Bernstein,H, AU - Bernstein,C, AU - Holubec,H, AU - Dvorakova,B, AU - Garewal,H, Y1 - 2006/08/03/ PY - 2006/8/5/pubmed PY - 2007/2/9/medline PY - 2006/8/5/entrez SP - 215 EP - 22 JF - Carcinogenesis JO - Carcinogenesis VL - 28 IS - 1 N2 - 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. SN - 0143-3334 UR - https://www.unboundmedicine.com/medline/citation/16887864/Deoxycholate_induces_mitochondrial_oxidative_stress_and_activates_NF_kappaB_through_multiple_mechanisms_in_HCT_116_colon_epithelial_cells_ L2 - https://academic.oup.com/carcin/article-lookup/doi/10.1093/carcin/bgl139 DB - PRIME DP - Unbound Medicine ER -