Regulation of Granulocyte Colony‐stimulating Factor and Parathyroid Hormonerelated Protein Production in Lung Carcinoma Cell Line OKa‐C‐1

Abstract

Previously we have established a clonal squamous cell carcinoma cell line OKa‐C‐1 derived from lung cancer of a patient with marked leukocytosis and hypercalcemia. OKa‐C‐1 cells simultaneously produce granulocyte colony‐stimulating factor (G‐CSF) and parathyroid hormone‐related protein (PTHrP) at the single cell level and cause paraneoplastic syndromes in nude mice bearing the tumor. It is known that the production of G‐CSF and PTHrP is individually regulated by inflammatory cytokines in various malignant cells. To investigate the common factors in the regulation of G‐CSF and PTHrP production in OKa‐C‐1 cells, we examined the effects of some inflammatory agents [lipopolysaccharide (LPS), phorbol‐12‐myristate‐13‐acetate (PMA), tumor necrosis factor‐α (TNF‐α), interleukin‐1 (IL‐1) β and IL‐6] on G‐CSF and PTHrP production, by means of enzyme‐linked immunosorbent assay (ELISA), immunoradiometric assay (IRMA) and quantitative reverse transcription‐polymerase chain reaction (RT‐PCR). TNF‐α or IL‐1β induced both G‐CSF and PTHrP production in the conditioned medium. TNF‐α synergized with IL‐1β to significantly increase G‐CSF production. In addition, TNF‐α and IL‐1β strongly induced G‐CSF mRNA with peaks at 2 and 6 h respectively. Although PTHrP production was also strongly induced by TNF‐α PTHrP mRNA expression was more strongly induced by PMA than by TNF‐α. Thus, TNF‐α and IL‐1β could be common factors that individually and synergistically regulate G‐CSF and PTHrP production in OKa‐C‐1 cells. Moreover, G‐CSF and PTHrP production could be not only transcriptionally, but also posttranscriptionally regulated by other factors.

A study of osteoclast-related cytokines in mandibular invasion by squamous cell carcinoma

“…The following eight cytokines were evaluated: Parathyroid hormone-related protein (PTHrP) 23 , tumor necrosis factor (TNF)-a 13 , interleukin (IL)-1a 3 , IL-1b 3 , IL-6 3 , IL-11 8 , IL-18 11 and transforming growth factor (TGF)-b 10 ( Table 1).…”

Establishment and Characterization of a New Lung Cancer Cell Line (MI‐4) Producing High Levels of Granulocyte Colony Stimulating Factor

“…[36][37][38] We have previously demonstrated that IL-1β and TNF-α significantly stimulate G-CSF production by the tumor cell line OKa-C-1. 39) In this study, we showed that both cytokines also significantly enhanced G-CSF production by MI-4 cells. MI-4 cells produced neither TNF-α nor IL-1β themselves.…”

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

“…[38][39][40] We showed that the inflammatory cytokines, TNF-α and IL-1β induced COX-2 expression in addition to G-CSF or GM-CSF in OKa-C-1 and MI-4 cells. 27,41) Some studies have reported that NF-κB activa- tion is required to upregulate G-CSF, GM-CSF, or COX-2 expression, [42][43][44][45][46][47][48][49] and that inactivation of the NF-κB also induces rapid pro-apoptotic action. 45) COX-2 activation was also shown to follow the activation of MAPK in another cell type.…”