Abstract
We previously established two lung cancer cell lines, OKa-C-1 and MI-4, which constitutively produce abundant granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF). Inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1beta stimulated the expression of G-CSF, GM-CSF, and cyclooxygenase (COX)-2 in the two cell lines. It is known that increased COX-2 activity promotes tumor growth and induces G-CSF and GM-CSF expression in non-malignant cells, and that selective COX-2 inhibitors inhibit the growth of some types of malignant cells. Therefore, we hypothesized that inhibition of COX-2 activity might suppress constitutive production of G-CSF or GM-CSF in addition to reducing the growth of malignant cells. We confirmed that the selective COX-2 inhibitor, NS-398 suppressed the constitutive production of G-CSF and GM-CSF, and the cell growth in both OKa-C-1 and MI-4 cell lines. Prostaglandin E2 (PGE2) reversed the inhibitions of G-CSF and GM-CSF expression, as well as cell growth, by NS-398. This result confirms that the effects of NS-398 are based on the inhibition of COX activity. Some studies have indicated that nuclear factor kappa B (NF-kappaB) or MAPK (mitogen-activated protein kinase) activation is related to upregulation of G-CSF, GM-CSF or COX-2 expression in some types of cells. Therefore, we examined if the actions of NS-398 might be mediated by the MAP kinase pathway or NF-kappaB activity in OKa-C-1 and MI-4 cells. We found that NS-398 inhibits G-CSF and GM-CSF production and cell growth through an extracellular signal-regulated kinase kinase (MEK) signaling pathway in these cell lines. The prognosis of non-small cell lung cancer showing G-CSF gene expression is significantly worse. G-CSF overproduction by tumor cells is observed at an advanced clinical stage. Our findings imply that a COX-2 inhibitor might improve the prognosis of patients with lung cancer through the reduction of G-CSF or GM-CSF.
MeSH terms
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Cell Division / drug effects
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / pharmacology*
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Dinoprostone / pharmacology
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Disease Progression
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Drug Screening Assays, Antitumor
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Enzyme Induction / drug effects
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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Gene Expression Regulation, Neoplastic / drug effects
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Granulocyte Colony-Stimulating Factor / biosynthesis*
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Granulocyte Colony-Stimulating Factor / genetics
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Granulocyte-Macrophage Colony-Stimulating Factor / biosynthesis*
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Granulocyte-Macrophage Colony-Stimulating Factor / genetics
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Humans
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Imidazoles / pharmacology
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Interleukin-1 / pharmacology
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Isoenzymes / antagonists & inhibitors*
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Isoenzymes / physiology
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Lung Neoplasms / pathology*
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MAP Kinase Signaling System / drug effects
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Membrane Proteins
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / metabolism
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology
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Nitrobenzenes / pharmacology*
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Proline / analogs & derivatives*
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Proline / pharmacology
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Prostaglandin-Endoperoxide Synthases / physiology
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Pyridines / pharmacology
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Recombinant Proteins / pharmacology
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Sulfonamides / pharmacology*
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Thiocarbamates / pharmacology
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / enzymology
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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Enzyme Inhibitors
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Flavonoids
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Imidazoles
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Interleukin-1
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Isoenzymes
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Membrane Proteins
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NF-kappa B
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Neoplasm Proteins
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Nitrobenzenes
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Pyridines
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Recombinant Proteins
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Sulfonamides
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Thiocarbamates
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Tumor Necrosis Factor-alpha
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N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
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prolinedithiocarbamate
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Granulocyte Colony-Stimulating Factor
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Granulocyte-Macrophage Colony-Stimulating Factor
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Proline
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase Kinases
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Dinoprostone
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SB 203580
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one