Cyclooxygenase‐2 inhibitor NS‐398 suppresses cell growth and constitutive production of granulocyte‐colony stimulating factor and granulocyte macrophage‐colony stimulating factor in lung cancer cells

• Published in: Cancer science Vol. 94; no. 2; pp. 173 - 180
• Main Authors: Nakata, Hideshi, Uemura, Yoshiki, Kobayashi, Makoto, Harada, Ryoji, Taguchi, Hirokuni
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.02.2003; Blackwell; John Wiley & Sons, Inc
• Subjects: Antineoplastic agents; Biological and medical sciences; Cell Division - drug effects; Cell growth; Colonies; Colony-stimulating factor; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - pharmacology; Dinoprostone - pharmacology; Disease Progression; Drug Screening Assays, Antitumor; Enzyme Induction - drug effects; Enzyme Inhibitors - pharmacology; Flavonoids - pharmacology; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; General aspects; Granulocyte Colony-Stimulating Factor - biosynthesis; Granulocyte Colony-Stimulating Factor - genetics; Granulocyte-Macrophage Colony-Stimulating Factor - biosynthesis; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Granulocytes; Humans; Imidazoles - pharmacology; Inflammation; Interleukin-1 - pharmacology; Isoenzymes - antagonists & inhibitors; Isoenzymes - physiology; Kinases; Leukocytes (granulocytic); Lung cancer; Lung Neoplasms - pathology; Macrophages; MAP kinase; MAP Kinase Signaling System - drug effects; Medical sciences; Membrane Proteins; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - metabolism; Mitogen-Activated Protein Kinases - metabolism; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; Nitrobenzenes - pharmacology; Non-small cell lung carcinoma; Pharmacology. Drug treatments; Prognosis; Proline - analogs & derivatives; Proline - pharmacology; Prostaglandin E2; Prostaglandin endoperoxide synthase; Prostaglandin-Endoperoxide Synthases - physiology; Protein kinase; Pyridines - pharmacology; Recombinant Proteins - pharmacology; Signal transduction; Sulfonamides - pharmacology; Thiocarbamates - pharmacology; Tumor cell lines; Tumor cells; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - enzymology; Tumor necrosis factor; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-TNF; Antineoplastic agent; Cell proliferation; Cyclooxygenase 2; Cyclooxygenase 2 inhibitor; Bronchopulmonary adenocarcinoma; Bronchopulmonary; Granulocyte colony stimulating factor; Established cell line; Bronchus disease; Inhibition; Human; Lung disease; Squamous cell carcinoma; Sulfonamide; Respiratory disease; Enzyme; Cytokine; Enzyme inhibitor; Mitogen-activated protein kinase; Malignant tumor; In vitro; Biological activity; Polypeptide; Oxidoreductases; Granulocyte macrophage colony stimulating factor
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/j.1349-7006.2003.tb01415.x

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‐α) and interleukin (IL)‐1β 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‐κB) or MARK (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‐κB 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. (Cancer Sci 2003; 94: 173–180)