Abstract
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-β1), 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.
Highlights
Garcinol (Figure 1) is isolated from the “Kokum” plant (Garcinia indica) that grows extensively on the western coast of India [1]
In our earlier work [14], we established that non-small cell lung cancer (NSCLC) A549 cells undergo Epithelial-to-mesenchymal transition (EMT) when exposed
EMT phenotype to cytotoxic effects of erlotinib as well as cisplatin; (ii) such sensitizing activity of garcinol involves potentiation of apoptosis-inducing activity of chemotherapy; (iii) garcinol induces the expression of tumor-suppressive miRNAs that regulate EMT; and (iv) the miRNAs, miR-200b and let-7c, are mechanistically involved in EMT suppressing and drug sensitizing activity of garcinol
Summary
Garcinol (Figure 1) is isolated from the “Kokum” plant (Garcinia indica) that grows extensively on the western coast of India [1]. The genus Garcinia includes some 200 species found in the tropics, especially Asia and Africa. Those from its rind, are rich in polyisoprenylated benzophenone derivatives, including garcinol. In our earlier studies on the anticancer property of garcinol, we demonstrated modulation of NF-κB
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