Journal Article

Curcumin (diferuloylmethane) down-regulates cigarette smoke-induced NF-κB activation through inhibition of IκBα kinase in human lung epithelial cells: correlation with suppression of COX-2, MMP-9 and cyclin D1

Shishir Shishodia, Pravin Potdar, C. Gary Gairola and Bharat B. Aggarwal

in Carcinogenesis

Volume 24, issue 7, pages 1269-1279
Published in print July 2003 | ISSN: 0143-3334
Published online July 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgg078
Curcumin (diferuloylmethane) down-regulates cigarette smoke-induced NF-κB activation through inhibition of IκBα kinase in human lung epithelial cells: correlation with suppression of COX-2, MMP-9 and cyclin D1

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Cigarette smoke (CS) is a major cause of a variety of malignancies including cancers of the larynx, oral cavity and pharynx, esophagus, pancreas, kidney, bladder and lung. The signal transduction pathway that mediates the effects of CS is not well understood but nuclear factor-kappa B (NF-κB) is probably involved. The gas phase of CS contains free radicals such as superoxide radicals, hydroxyl radicals and hydrogen peroxide, which potentially can activate NF-κB. Benzo[a]pyrene, another potent carcinogen of CS, can also activate NF-κB, but by an as yet unknown mechanism. Various other agents that activate NF-κB are either tumor initiators or tumor promoters, and NF-κB activation can block apoptosis, promote proliferation and mediate tumorigenesis. Therefore, NF-κB is an ideal target for preventing CS-induced lung carcinogenesis. Thus, agents that abrogate NF-κB activation have the potential to suppress lung carcinogenesis. Because curcumin, a diferuloylmethane, is anticarcinogenic, we investigated the effect of this phytochemical on CS-induced NF-κB activation and NF-κB-regulated gene expression in human non-small cell lung carcinoma cells. Exposure of cells to CS induced persistent activation of NF-κB, and pre-treatment with curcumin abolished the CS-induced DNA-binding of NF-κB, IκBα kinase activation, IkBα phosphorylation and degradation, p65 nuclear translocation and CS-induced NF-κB-dependent reporter gene expression. The inhibition of NF-κB activation correlated with suppression of CS-induced NF-κB-dependent cyclin D1, cyclooxygenase-2 and matrix metalloproteinase-9 expression. Overall our results indicate that CS-induced NF-κB activation and NF-κB-regulated gene expression in human non-small cell lung carcinoma cells is suppressed by curcumin through suppression of IκBα kinase.

Keywords: B[a]P, benzo[a]pyrene; COX-2, cyclooxygenase-2; CS, cigarette smoke; CSC, cigarette smoke condensate; EMSA, electrophoretic mobility shift assay; IκB, inhibitory subunit of NF-κB; IKK, IκBα kinase; NF-κB, nuclear factor-kappa B; MMP-9, matrix metalloproteinase-9; SDS, sodium dodecyl sulfate; SEAP, secretory alkaline phosphatase; TNF, tumor necrosis factor

Journal Article.  7362 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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