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. 2005 Aug 19;94(2):173–180. doi: 10.1111/j.1349-7006.2003.tb01415.x

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

Hideshi Nakata 1, Yoshiki Uemura 1,1, Makoto Kobayashi 1, Ryoji Harada 1, Hirokuni Taguchi 1
PMCID: PMC11160091  PMID: 12708493

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‐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)

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