title: Vascular endothelial growth factor induces CXCL1 chemokine release via JNK and PI-3K-dependent pathways in human lung carcinoma epithelial cells.
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.
authors.affiliation: School of Medicine, Fu-Jen Catholic University, New Taipei City 24205, Taiwan. wenbin@mail.fju.edu.tw.
authors.forename: Huey-Ming
authors.initials: HM
authors.lastname: Lo
authors.forename: Jiunn-Min
authors.initials: JM
authors.lastname: Shieh
authors.forename: Chih-Li
authors.initials: CL
authors.lastname: Chen
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Tsou
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Wu
mesh_terms: D045744:Cell Line, Tumor; D054360:Chemokine CXCL1 / Q000235:genetics / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D020935:MAP Kinase Signaling System; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology*; D015398:Signal Transduction; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology*
chemical_list: D054360:Chemokine CXCL1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019869:Phosphatidylinositol 3-Kinases