Nobiletin Inhibits Angiogenesis by Regulating Src/FAK/STAT3-Mediated Signaling through PXN in ER⁺ Breast Cancer Cells.
Nobiletin Inhibits Angiogenesis by Regulating Src/FAK/STAT3-Mediated Signaling through PXN in ER⁺ Breast Cancer Cells.
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DOI：
10.3390/ijms18050935
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发表时间：
2017-04-30
影响因子：
5.6
通讯作者：
Yang YM
中科院分区：
文献类型：
--
作者：
Sp N;Kang DY;Joung YH;Park JH;Kim WS;Lee HK;Song KD;Park YM;Yang YM
肿瘤血管生成是肿瘤进展的主要标志之一。诺比莱汀是从柑橘皮中分离得到的一种具有抗血管生成活性的天然黄酮类化合物。类固醇受体辅活化子(Src)是一种细胞内酪氨酸激酶，通过粘着斑激酶(FAK)与Src结合，在肿瘤血管生成中发挥作用。信号转导和转录激活因子3(STAT3)是与Src相互作用的肿瘤血管生成的标志物。PXN是FAK和STAT3的下游靶点。本研究的主要目的是通过PXN评估nobiletin对雌激素受体阳性(ER+)乳腺癌细胞中肿瘤血管生成的抑制作用。根据Western blotting和RT-PCR，nobiletin对MCF-7和T47D乳腺癌细胞的治疗抑制了血管生成标记物。人脐静脉内皮细胞系(HUVEC)的体外血管生成实验证实了nobiletin的抗血管生成活性。凝胶迁移率改变分析和芯片分析表明，nobiletin抑制了STAT3/DNA结合活性和STAT3与PXN基因启动子新的结合部位的结合。我们还研究了nobiletin在ER+细胞中的迁移和侵袭能力。Nobiletin通过PXN调节ER+乳腺癌细胞中的Src、FAK和STAT3信号，从而抑制肿瘤血管生成。
Tumor angiogenesis is one of the major hallmarks of tumor progression. Nobiletin is a natural flavonoid isolated from citrus peel that has anti-angiogenic activity. Steroid receptor coactivator (Src) is an intracellular tyrosine kinase so that focal adhesion kinase (FAK) binds to Src to play a role in tumor angiogenesis. Signal transducer and activator of transcription 3 (STAT3) is a marker for tumor angiogenesis which interacts with Src. Paxillin (PXN) acts as a downstream target for both FAK and STAT3. The main goal of this study was to assess inhibition of tumor angiogenesis by nobiletin in estrogen receptor positive (ER+) breast cancer cells via Src, FAK, and STAT3-mediated signaling through PXN. Treatment with nobiletin in MCF-7 and T47D breast cancer cells inhibited angiogenesis markers, based on western blotting and RT-PCR. Validation of in vitro angiogenesis in the human umbilical vein endothelial cells (HUVEC) endothelial cell line proved the anti-angiogenic activity of nobiletin. Electrophoretic mobility shift assay and the ChIP assay showed that nobiletin inhibits STAT3/DNA binding activity and STAT3 binding to a novel binding site of the PXN gene promoter. We also investigated the migration and invasive ability of nobiletin in ER+ cells. Nobiletin inhibited tumor angiogenesis by regulating Src, FAK, and STAT3 signaling through PXN in ER+ breast cancer cells.