Abstract: Lung cancer cells express different chemokines and chemokine receptors that modulate leukocyte infiltration within tumor microenvironment. In this study we screened several mediators/growth factors on CXCL1 release in human carcinoma epithelial cells. Of the tested mediators, VEGF was found to have a robust increase in causing CXCL1 release. VEGF stimulated CXCL1 release and mRNA expression in a time- and concentration-dependent manner. The release was inhibited by the VEGF receptor antagonists and the JNK, PI-3K, tyrosine kinase, and transcription inhibitors. In parallel, VEGF induced JNK, PI3K and Akt activation. Strikingly, among these inhibitors only the JNK inhibitor could reduce VEGF-induced CXCL1 mRNA expression, suggesting that JNK participated in VEGF-induced CXCL1 synthesis, whereas PI-3K was responsible for cellular CXCL1 secretory process. In addition, the steroid dexamethasone and TGF-β suppressed CXCL1 release through a transcriptional regulation. We also showed that cells stimulated with VEGF significantly attracted monocyte migration, which could be abolished by CXCL1 B/N Ab, CXC receptor 2 antagonist, TGF-β, and dexamethasone. In summary, we provide here evidence showing JNK activation for VEGF-induced CXCL1 DNA transcription and PI-3K pathway for extracellular CXCL1 release in human carcinoma epithelial cells. The released CXCL1 was functionally linked to recruiting monocytes into lung cancer cell microenvironment.
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Lo, H.-M.; Shieh, J.-M.; Chen, C.-L.; Tsou, C.-J.; Wu, W.-B. Vascular Endothelial Growth Factor Induces CXCL1 Chemokine Release via JNK and PI-3K-Dependent Pathways in Human Lung Carcinoma Epithelial Cells. Int. J. Mol. Sci. 2013, 14, 10090-10106.
Lo H-M, Shieh J-M, Chen C-L, Tsou C-J, Wu W-B. Vascular Endothelial Growth Factor Induces CXCL1 Chemokine Release via JNK and PI-3K-Dependent Pathways in Human Lung Carcinoma Epithelial Cells. International Journal of Molecular Sciences. 2013; 14(5):10090-10106.
Lo, Huey-Ming; Shieh, Jiunn-Min; Chen, Chih-Li; Tsou, Chih-Jen; Wu, Wen-Bin. 2013. "Vascular Endothelial Growth Factor Induces CXCL1 Chemokine Release via JNK and PI-3K-Dependent Pathways in Human Lung Carcinoma Epithelial Cells." Int. J. Mol. Sci. 14, no. 5: 10090-10106.