Caffeic acid and its synthetic derivative CADPE suppress tumor angiogenesis by blocking STAT3-mediated VEGF expression in human renal carcinoma cells
Caffeic acid and its synthetic derivative CADPE suppress tumor angiogenesis by blocking STAT3-mediated VEGF expression in human renal carcinoma cells
复制标题
DOI：
10.1093/carcin/bgm130
复制
发表时间：
2007-08-01
期刊：
影响因子：
4.7
通讯作者：
Chung, Myung-Hee
中科院分区：
文献类型：
--
作者：
Jung, Joo Eun;Kim, Hong Sook;Chung, Myung-Hee
肿瘤血管生成是肿瘤发展所必需的，并且由血管生成诱导剂如VEGF（血管内皮生长因子）刺激。我们的前期研究表明，STAT 3（signal transducer and activator of transcription 3）上调缺氧实体瘤细胞中HIF-1 α（hypoxia inducible factor-lot）蛋白的稳定性，并增强HIF-1介导的VEGF表达，提示抑制STAT 3信号通路可能具有临床应用价值。在这项研究中，我们研究了在体外和体内，是否咖啡酸（CA）或其衍生物CADPE [3-（3，4-二羟基-苯基）-丙烯酸2-（3，4-二羟基-苯基）-乙酯]发挥抗癌活性，通过靶向STAT 3。发现CA或CADPE显著抑制STAT 3活性，并且这反过来下调HIEF-1 α活性。因此，STAT 3和HIEF-1 α的顺序阻断通过抑制它们向VEGF启动子的募集而导致VEGF的下调。在携带Caki-I癌的小鼠中，CA和CADPE均延缓肿瘤生长并抑制肿瘤中的STAT 3磷酸化、HIF-1 α表达、血管形成和STAT 3诱导的VEGF基因表达。综上所述，我们的研究结果表明，CA和CADPE是STAT 3的潜在抑制剂，它们通过抑制STAT 3的活性、HIF-1 α和VEGF的表达来抑制肿瘤血管生成。
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 alpha (hypoxia inducible factor-lot) 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-(3,4dihydroxy-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 HIEF-1 alpha activity. Consequently, sequential blockade of STAT3 and HIEF-1 alpha 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 alpha 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 alpha and VEGF.