title: Caffeic acid and its synthetic derivative CADPE suppress tumor angiogenesis by blocking STAT3-mediated VEGF expression in human renal carcinoma cells.
abstract: 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-1alpha (hypoxia inducible factor-1alpha) 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-1alpha activity. Consequently, sequential blockade of STAT3 and HIF-1alpha 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-1alpha 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-1alpha and VEGF.
authors.affiliation: Department of Pharmacology, College of Medicine, Seoul National University, Seoul 110-799, Korea.
authors.forename: Joo Eun
authors.initials: JE
authors.lastname: Jung
authors.forename: Hong Sook
authors.initials: HS
authors.lastname: Kim
authors.forename: Chang Seok
authors.initials: CS
authors.lastname: Lee
authors.forename: Dae-Hun
authors.initials: DH
authors.lastname: Park
authors.forename: Yong-Nyun
authors.initials: YN
authors.lastname: Kim
authors.forename: Min-Jae
authors.initials: MJ
authors.lastname: Lee
authors.forename: Jung Weon
authors.initials: JW
authors.lastname: Lee
authors.forename: Jong-Wan
authors.initials: JW
authors.lastname: Park
authors.forename: Myung-Suk
authors.initials: MS
authors.lastname: Kim
authors.forename: Sang Kyu
authors.initials: SK
authors.lastname: Ye
authors.forename: Myung-Hee
authors.initials: MH
authors.lastname: Chung
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019556:COS Cells; D002109:Caffeic Acids / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
chemical_list: C523599:3-(3,4-dihydroxyphenyl)acrylic acid 2-(3,4-dihydroxyphenyl)ethyl ester; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D002109:Caffeic Acids; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D042461:Vascular Endothelial Growth Factor A; C040048:caffeic acid