Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
Chem Biol Interact. 2019 Apr 25;303:14-21. doi: 10.1016/j.cbi.2019.02.020. Epub 2019 Feb 22.
Fisetin (3,3',4',7-tetrahydroxyflavone) is a bioactive polyphenolic flavonoid found in many fruits and vegetables. It exhibits a variety of pharmacological activities including anticancer and anti-invasive effects. Epithelial to mesenchymal transition (EMT) allows the tumor cells to acquire increased migratory and invasive properties mediating their dissemination to faraway sites, thus favoring metastasis. With metastatic lung cancer claiming the majority of lung cancer-related deaths, agents targeting the pathways underlying metastasis are translationally promising. In the present study, we have explored the anti-metastatic effects of fisetin in non-small cell lung carcinoma (NSCLC) cells A549 and H1299 with emphasis on EMT. The results suggested a significant inhibition in migration and invasion of NSCLC cells under non-cytotoxic concentrations. Furthermore, an attenuation of the EMT was observed in both the cell lines with upregulation in the expression of epithelial marker E-cadherin in A549 cells and ZO-1 in H1299 cells with concomitant downregulation of the mesenchymal markers vimentin as well as N-cadherin along with invasion marker MMP-2. Herein, the downregulation of the expression of NSCLC stem cell signature markers CD44 and CD133 was also observed. Fisetin decreased the expression of multiple signaling proteins (β-catenin, NF-κB, EGFR, STAT-3) acting upstream to EMT and known to be involved in induction and maintenance of mesenchymal phenotype, which may explain the observed effects. Moreover, fisetin decreased the ability of H1299 cells to form colonies on soft agar and potentiated the cytotoxic effects of tyrosine kinase inhibitor (TKI), erlotinib. Overall, our study suggested the ability of fisetin to serve as a potential therapeutic agent on its capacity to attenuate the EMT program and inhibit migration, invasion and stem cell phenotype of lung cancer cells.
漆黄素（3,3',4',7-四羟基黄酮）是一种存在于许多水果和蔬菜中的生物活性多酚类黄酮。它具有多种药理活性，包括抗癌和抗侵袭作用。上皮间质转化（EMT）使肿瘤细胞获得增加的迁移和侵袭特性，介导其向远处部位的扩散，从而有利于转移。转移性肺癌导致大多数与肺癌相关的死亡，因此靶向转移相关途径的药物具有转化潜力。在本研究中，我们探讨了漆黄素在非小细胞肺癌（NSCLC）细胞 A549 和 H1299 中的抗转移作用，重点是 EMT。结果表明，在非细胞毒性浓度下，NSCLC 细胞的迁移和侵袭明显受到抑制。此外，在这两种细胞系中都观察到 EMT 的衰减，A549 细胞中上皮标志物 E-钙粘蛋白的表达上调，H1299 细胞中 ZO-1 的表达上调，同时间充质标志物波形蛋白以及 N-钙粘蛋白的表达下调，侵袭标志物 MMP-2 也下调。此外，还观察到 NSCLC 干细胞标志物 CD44 和 CD133 的表达下调。漆黄素下调 EMT 上游的多种信号蛋白（β-连环蛋白、NF-κB、EGFR、STAT-3）的表达，这些蛋白已知参与诱导和维持间充质表型，这可能解释了观察到的效应。此外，漆黄素降低了 H1299 细胞在软琼脂上形成集落的能力，并增强了酪氨酸激酶抑制剂（TKI）厄洛替尼的细胞毒性作用。总之，我们的研究表明，漆黄素具有作为一种潜在治疗剂的能力，能够减轻 EMT 程序并抑制肺癌细胞的迁移、侵袭和干细胞表型。
