Carcinogenesis Advance Access originally published online on June 8, 2007
Carcinogenesis 2007 28(8):1780-1787; 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
Department of Pharmacology, College of Medicine, Seoul National University, Seoul 110-799, Korea
1 Division of Cancer Experimental Resources Branch
2 Pediatric Oncology Branch, Division of Specific Organs Center, National Cancer Center, Goyang 410-769, Korea
3 Department of Veterinary Lab Animal Medicine and Science, Kangwon National University, Chunchun 200-701, Korea
4 Department of Tumor Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea
* To whom correspondence should be addressed. Tel: +82 2 740 8281; Fax: +82 2 740 7996;Email: 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.
Abbreviations: CA, caffeic acid; CADPE, 3-(3,4-Dihydroxy-phenyl)-acrylic acid 2-(3,4-dihydroxy-phenyl)-ethyl ester; CAPE, caffeic acid phenetyl ester; DMSO, dimethyl sulfoxide; EDTA, ethylenediaminetetraacetic acid; EGTA, ethyleneglycol-bis(aminoethylether)-tetraacetic acid; STAT3, signal transducer and activator of transcription 3; HIF-1, hypoxia-inducible factor-1; VEGF, vascular endothelial growth factor
Received November 28, 2006; revised May 17, 2007; accepted May 23, 2007.