A Small-Molecule Triptolide Suppresses Angiogenesis and Invasion of Human Anaplastic Thyroid Carcinoma Cells via Down-Regulation of the Nuclear Factor-κB Pathway
A Small-Molecule Triptolide Suppresses Angiogenesis and Invasion of Human Anaplastic Thyroid Carcinoma Cells via Down-Regulation of the Nuclear Factor-κB Pathway
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DOI：
10.1124/mol.108.052605
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发表时间：
2009-04-01
影响因子：
3.6
通讯作者：
Yan, Guangmei
中科院分区：
文献类型：
--
作者：
Zhu, Wenbo;Ou, Yanqiu;Yan, Guangmei
间变性甲状腺癌（ATC）是已知最具侵袭性的恶性肿瘤之一，其特点是生长迅速，侵袭早期，对目前的治疗完全难治。在这里，我们报道了雷公藤甲素，一种来自中草药的小分子，可以在纳米摩尔浓度下有效抑制人ATC细胞系TA-K细胞的体外增殖、体内血管生成和Matrigel模型中的侵袭。我们进一步阐明，雷公雷甲素在早期通过阻断p65亚基与creb结合蛋白(CBP)/p300的关联，在晚期通过降低p65的蛋白水平，抑制核因子κ B（NF κ B）的转录活性。tnf - κ B靶向基因cyclin D1、血管内皮生长因子和尿激酶型纤溶酶原激活因子在TA-K和8505C人ATC细胞系中的表达被雷公雷甲素显著降低，而这些基因对于实体肿瘤的增殖、血管生成和侵袭至关重要。我们的研究结果表明雷公藤甲素可能作为肿瘤血管生成和侵袭的小分子抑制剂，并可能为人类ATC的潜在治疗提供新的机制见解。
Anaplastic thyroid carcinoma (ATC) is among the most aggressive malignancies known and is characterized with rapid growth, early invasion, and complete refractoriness to current therapies. Here we report that triptolide, a small molecule from a Chinese herb, could potently inhibit proliferation in vitro, angiogenesis in vivo, and invasion in a Matrigel model in human ATC cell line TA-K cells at nanomolar concentrations. We further elucidate that triptolide inhibits the nuclear factor-kappa B(NF kappa B) transcriptional activity via blocking the association of p65 subunit with CREB-binding protein (CBP)/p300 in the early stage and via decreasing the protein level of p65 in the late stage. Expression of the NF-kappa B targeting genes cyclin D1, vascular endothelial growth factor, and urokinase-type plasminogen activator is significantly reduced by triptolide in both TA-K and 8505C human ATC cell lines, which are well known to be critical for proliferation, angiogenesis, and invasion in solid tumors. Our findings suggest that triptolide may function as a small molecule inhibitor of tumor angiogenesis and invasion and may provide novel mechanistic insights into the potential therapy for human ATC.