Garcinol Sensitizes NSCLC Cells to Standard Therapies by Regulating EMT-Modulating miRNAs
Garcinol Sensitizes NSCLC Cells to Standard Therapies by Regulating EMT-Modulating miRNAs
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DOI：
10.3390/ijms20040800
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发表时间：
2019-02-02
影响因子：
5.6
通讯作者：
Ahmad, Aamir
中科院分区：
文献类型：
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作者：
Farhan, Mohd;Malik, Arshi;Ahmad, Aamir
Garcinol是一种从Garcinia indica中获得的膳食因子，可调节几种关键的细胞信号传导途径以及miRNA的表达。对标准疗法（如厄洛替尼和顺铂）的获得性抗性是非小细胞肺癌（NSCLC）细胞的标志，其通常涉及miRNA调节的上皮向间充质转化（EMT）。我们使用了暴露于转化生长因子β 1（TGF-1）的A549细胞，产生了具有间充质和耐药表型的A549 M细胞，并报告说加西醇使具有间充质表型的耐药细胞对厄洛替尼和顺铂敏感，其IC 50值显着降低。它还增强了厄洛替尼在A549 M和内源性间充质H1299 NSCLC细胞中的凋亡诱导活性。此外，Garcinol显著上调了几种关键的EMT调节miRNA，如miR-200 b，miR-205，miR-218和let-7 c。通过抗miRNA转染，拮抗性miRNA减弱了Garcinol的EMT调节活性，如通过EMT标志物、E-钙粘蛋白、波形蛋白和锌指E盒结合同源异型盒1（ZEB 1）的mRNA表达所确定的。这进一步导致厄洛替尼的抑制以及顺铂敏化，从而确立了miRNA，特别是miR-200 c和let-7 c在加西诺介导的EMT逆转和NSCLC细胞对标准疗法的敏化中的机制作用。
Garcinol, a dietary factor obtained from Garcinia indica, modulates several key cellular signaling pathways as well as the expression of miRNAs. Acquired resistance to standard therapies, such as erlotinib and cisplatin, is a hallmark of non-small cell lung cancer (NSCLC) cells that often involves miRNA-regulated epithelial-to-mesenchymal transition (EMT). We used A549 cells that were exposed to transforming growth factor beta 1 (TGF-1), resulting in A549M cells with mesenchymal and drug resistant phenotype, and report that garcinol sensitized resistant cells with mesenchymal phenotype to erlotinib as well as cisplatin with significant decrease in their IC50 values. It also potentiated the apoptosis-inducing activity of erlotinib in A549M and the endogenously mesenchymal H1299 NSCLC cells. Further, garcinol significantly upregulated several key EMT-regulating miRNAs, such as miR-200b, miR-205, miR-218, and let-7c. Antagonizing miRNAs, through anti-miRNA transfections, attenuated the EMT-modulating activity of garcinol, as determined by mRNA expression of EMT markers, E-cadherin, vimentin, and Zinc Finger E-Box Binding Homeobox 1 (ZEB1). This further led to repression of erlotinib as well as cisplatin sensitization, thus establishing the mechanistic role of miRNAs, particularly miR-200c and let-7c, in garcinol-mediated reversal of EMT and the resulting sensitization of NSCLC cells to standard therapies.