Abstract
Tissue factor (TF) plays an important role in the progression and angiogenesis of tumor cells. The present study investigated the mechanism of interleukin-1β (IL-1β)-induced TF expression in A549 lung cancer cells. Based on mRNA and protein analyses, including appropriate inhibitor experiments, IL-1β was shown to induce TF expression in a time-dependent manner, mediated by IL-1 receptor-dependent phosphorylation of the mitogen-activated protein kinases (MAPK) p38, p42/44 and c-jun N-terminal kinase (JNK), as well as the Src kinase and the epidermal growth factor receptor (EGFR). Thereby, inhibition of EGFR transactivation by the Src inhibitor PP1 or direct EGFR inhibition by the EGFR tyrosine kinase inhibitor (TKI) erlotinib led to a reduction of IL-1β-induced TF expression and to a suppression of p42/44 MAPK and EGFR activation, while IL-1β-induced p38 MAPK and JNK activation remained unchanged. A knockdown of EGFR by siRNA was associated with decreased IL-1β-mediated p42/44 MAPK activation, which was no longer inhibitable by erlotinib. Concentration-dependent inhibition of IL-1β-induced TF expression was also observed in the presence of gefitinib and afatinib, two other EGFR TKIs. In summary, our results suggest that IL-1β leads to increased TF formation in lung cancer cells via both Src/EGFR/p42/44 MAPK-dependent and EGFR-independent signaling pathways, with the latter mediated via p38 MAPK and JNK.
Highlights
The tissue factor represents a 47-kDa transmembrane glycoprotein, which is considered the primary initiator of blood coagulation [1,2,3]
In order to obtain the first indications of the mechanism of Tissue factor (TF) induction, inhibitor experiments with the IL-1 receptor antagonist (IL-1Ra) and with inhibitors of mitogen-activated protein kinases (MAPK) were performed
Thereby, IL-1Ra induced a complete blockade of IL-1β-induced TF formation (Figure 1C), while inhibitors of p38 MAPK (SB203580) and jun N-terminal kinase (JNK) (SP600125) as well as an inhibitor of p42/44 MAPK activation (PD98059) induced partial but significant suppression of TF protein production (Figure 1D)
Summary
The tissue factor represents a 47-kDa transmembrane glycoprotein, which is considered the primary initiator of blood coagulation [1,2,3]. With regard to the molecular mechanism, it has been shown, for example, that TF in the form of the binary TF-FVIIa and the ternary TF-FVIIa-FXa complex leads to an induction of cancer cell proliferation and migration via activation of the protease-activated receptor (PAR)-2 [8,9]. Together, these properties make TF a potential target for cancer therapy [6,7]. One study suggested that TF gene expression could be used as a prognostic marker in NSCLC [13]
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