Curcumin (diferuloylmethane) down-regulates cigarette smoke-induced NF-kappaB activation through inhibition of IkappaBalpha kinase in human lung epithelial cells: correlation with suppression of COX-2, MMP-9 and cyclin D1.
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-kappaB) 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-kappaB. Benzo[a]pyrene, another potent carcinogen of CS, can also activate NF-kappaB, but by an as yet unknown mechanism. Various other agents that activate NF-kappaB are either tumor initiators or tumor promoters, and NF-kappaB activation can block apoptosis, promote proliferation and mediate tumorigenesis. Therefore, NF-kappaB is an ideal target for preventing CS-induced lung carcinogenesis. Thus, agents that abrogate NF-kappaB 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-kappaB activation and NF-kappaB-regulated gene expression in human non-small cell lung carcinoma cells. Exposure of cells to CS induced persistent activation of NF-kappaB, and pre-treatment with curcumin abolished the CS-induced DNA-binding of NF-kappaB, IkappaBalpha kinase activation, IkBalpha phosphorylation and degradation, p65 nuclear translocation and CS-induced NF-kappaB-dependent reporter gene expression. The inhibition of NF-kappaB activation correlated with suppression of CS-induced NF-kappaB-dependent cyclin D1, cyclooxygenase-2 and matrix metalloproteinase-9 expression. Overall our results indicate that CS-induced NF-kappaB activation and NF-kappaB-regulated gene expression in human non-small cell lung carcinoma cells is suppressed by curcumin through suppression of IkappaBalpha kinase.
Shishodia
Shishir
S
Cytokine Research Laboratory, Department of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center, Box 143, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Potdar
Pravin
P
Gairola
C Gary
CG
Aggarwal
Bharat B
BB
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology*; D019938:Cyclin D1 / Q000378:metabolism; D051546:Cyclooxygenase 2; D017931:DNA Primers / Q000737:chemistry; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase; D007527:Isoenzymes / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008565:Membrane Proteins; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking / Q000009:adverse effects*; D014162:Transfection
D000970:Antineoplastic Agents; D017931:DNA Primers; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D019938:Cyclin D1; D008156:Luciferases; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D020780:Matrix Metalloproteinase 9; D003474:Curcumin