Carcinogenesis Advance Access published online on June 8, 2007
Carcinogenesis, doi:10.1093/carcin/bgm130
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Caffeic Acid and its Synthetic Derivative CADPE Suppress Tumor Angiogenesis by Blocking STAT3-mediated VEGF Expression in Human Renal Carcinoma Cells
1 Department of Pharmacology, College of Medicine, Seoul National University, Seoul, Korea
2 National Cancer Center, Divisions of Cancer Experimental Resources Branch, Goyang, Korea
3 Specific Organs Center, Pediatric Oncology Branch, Goyang, Korea
4 Department of Veterinary Lab Animal Medicine & Science, Kangwon National University, Chunchun, Korea
5 Cancer Institute, Department of Tumor Biology, Seoul National University College of Medicine, Seoul, Korea
* Corresponding author: Sang-Kyu Ye, E-mail; sangkyu{at}snu.ac.kr
Tumor angiogenesis is required for tumor development and is stimulated by angiogenic inducers like VEGF (vascular endothelial growth factor). Our previous study demonstrated that STAT3 (signal transducer and activator of transcription 3) up-regulates HIF-1
(hypoxia inducible factor-1) protein stability and enhances HIF-1-mediated VEGF expression in hypoxic solid tumor cells, thus suggesting that the inhibition of STAT3 signaling may have clinical applications. In this study, we examined in vitro and in vivo, whether caffeic acid (CA) or its derivative CADPE (3-(3, 4-dihydroxy-phenyl)-acrylic acid 2-(3, 4-dihydroxy-phenyl)-ethyl ester) exert anticancer activity by targeting STAT3. It was found that CA or CADPE significantly inhibit STAT3 activity, and that this in turn down-regulates HIF-1 activity. Consequently, sequential blockade of STAT3 and HIF-1 resulted in the down-regulation of VEGF by inhibiting their recruitment to the VEGF promoter. In mice bearing a Caki-I carcinoma, both CA and CADPE retarded tumor growth and suppressed STAT3 phosphorylation, HIF-1 expression, vascularization, and STAT3-inducible VEGF gene expression in tumors. Taken together, our results demonstrate that CA and CADPE are potential inhibitors of STAT3, and that they suppress tumor angiogenesis by inhibiting the activity of STAT3, the expression of HIF-1 and VEGF.
Key Words: CADPE • STAT3 • HIF-1 • VEGF • Tumor angiogenesis
Received November 28, 2006; revised May 17, 2007; accepted May 23, 2007.
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