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

Huey-Ming Lo²  Jiunn-Min Shieh¹  Chih-Li Chen²  Chih-Jen Tsou² 

[1] Department of Internal Medicine, Chi-Mei Medical Center, Tainan 71004, Taiwan; E-Mail:;School of Medicine, Fu-Jen Catholic University, New Taipei City 24205, Taiwan; E-Mails:

关键词: A549;    chemokine;    CXCL1;    GRO alpha;    signaling;    VEGF;   

DOI  :  10.3390/ijms140510090

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland