Baicalein inhibits fibronectin-induced epithelial-mesenchymal transition by decreasing activation and upregulation of calpain-2
Baicalein inhibits fibronectin-induced epithelial-mesenchymal transition by decreasing activation and upregulation of calpain-2
复制标题
黄芩素通过减少 calpain-2 的激活和上调来抑制纤连蛋白诱导的上皮-间质转化
DOI：
10.1038/s41419-019-1572-7
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发表时间：
2019-04-18
影响因子：
9
通讯作者：
Shen, Xiangchun
中科院分区：
文献类型：
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作者：
Chen, Yan;Chen, Lin;Shen, Xiangchun
细胞外基质蛋白纤连蛋白（FN）促进肿瘤发生和乳腺癌的发展。抑制FN诱导的细胞反应是乳腺癌治疗的潜在策略。在本研究中，我们研究了黄酮黄芩素对FN诱导的MCF-10A乳腺上皮细胞和转基因小鼠MMTV-Polyoma中T抗原乳腺癌模型（MMTV-PyMT）中的上皮-间质转化（EMT）的影响。黄芩素抑制FN诱导的迁移、侵袭和F-actin重塑。黄芩素还抑制FN诱导的上皮标志物E-钙粘蛋白和ZO-1的下调以及间充质标志物N-钙粘蛋白、波形蛋白和Snail的上调。进一步的研究表明calpain-2参与了黄芩素抑制FN诱导的EMT。黄芩素通过抑制钙蛋白酶-2的质膜定位、底物裂解和内源性抑制剂钙蛋白酶抑制蛋白的降解，显著降低FN增强的钙蛋白酶-2的表达和活化。钙蛋白酶-2基因转染MCF-10A细胞可部分阻断黄芩素对FN诱导的EMT改变的抑制作用。此外，黄芩素通过降低FN增加的细胞内钙离子水平和细胞外信号调节蛋白激酶的激活来抑制钙蛋白酶-2。黄芩素显著降低自发性乳腺癌MMTV-PyMT小鼠模型中的肿瘤发生、生长和肺转移。黄芩素还降低FN、钙蛋白酶-2和波形蛋白的表达，但增加MMTV-PyMT小鼠肿瘤中E-钙粘蛋白的表达。这些结果表明黄芩素通过抑制calpain-2显著抑制FN诱导的EMT，从而为黄芩素的药理作用和机制提供了新的见解。因此，黄芩素可能具有治疗乳腺癌的治疗潜力，虽然干扰细胞外基质-癌细胞的相互作用。
The extracellular matrix protein fibronectin (FN) facilitates tumorigenesis and the development of breast cancer. Inhibition of the FN-induced cellular response is a potential strategy for breast cancer treatment. In the present study, we investigated the effects of the flavonoid baicalein on FN-induced epithelial–mesenchymal transition (EMT) in MCF-10A breast epithelial cells and in a transgenic mouse MMTV-polyoma middle T antigen breast cancer model (MMTV-PyMT). Baicalein inhibited FN-induced migration, invasion, and F-actin remodeling. Baicalein also suppressed FN-induced downregulation of the epithelial markers E-cadherin and ZO-1 and upregulation of the mesenchymal markers N-cadherin, vimentin, and Snail. Further investigation revealed that calpain-2 was involved in baicalein suppression of FN-induced EMT. Baicalein significantly decreased FN-enhanced calpain-2 expression and activation by suppressing its plasma membrane localization, substrate cleavage, and degradation of its endogenous inhibitor calpastatin. Overexpression of calpain-2 in MCF-10A cells by gene transfection partially blocked the inhibitory effect of baicalein on FN-induced EMT changes. In addition, baicalein inhibited calpain-2 by decreasing FN-increased intracellular calcium ion levels and extracellular signal-regulated protein kinases activation. Baicalein significantly decreased tumor onset, growth, and pulmonary metastasis in a spontaneous breast cancer MMTV-PyMT mouse model. Baicalein also reduced the expression of FN, calpain-2, and vimentin, but increased E-cadherin expression in MMTV-PyMT mouse tumors. Overall, these results revealed that baicalein markedly inhibited FN-induced EMT by inhibiting calpain-2, thus providing novel insights into the pharmacological action and mechanism of baicalein. Baicalein may therefore possess therapeutic potential for the treatment of breast cancer though interfering with extracellular matrix–cancer cell interactions.