Garcinol Sensitizes NSCLC Cells to Standard Therapies by Regulating EMT-Modulating miRNAs

International Journal of Molecular Sciences

卷:20

Sarah Afaq¹  Arshi Malik¹  Mohd Farhan²  MohammadFahad Ullah³  Aamir Ahmad⁴  Mohd Faisal⁵  AmmadAhmad Farooqi⁶  Bernhard Biersack⁷  Rainer Schobert⁷ 

[1] Clinical Biochemistry, College of Medicine, King Khalid University, Abha 62529, Saudi Arabia;

[2] College of Basic Sciences, King Faisal University, Hofuf, 400, Al Ahsa 31982, Saudi Arabia;

[3] Department of Medical Laboratory Technology, Faculty of Applied Medical Science, University of Tabuk, Tabuk 71491, Saudi Arabia;

[4] Department of Pathology, Wayne State University and Karmanos Cancer Institute, Detroit, MI 48201, USA;

[5] Department of Psychiatry, University Hospital Limerick, Limerick V94 T9PX, Ireland;

[6] Institute of Biomedical and Genetic Engineering (IBGE), Islamabad 44000, Pakistan;

[7] Organic Chemistry Laboratory, Universitätsstr. 30, 95447 Bayreuth, Germany;

关键词: garcinol;    NSCLC;    EMT;    erlotinib;    cisplatin;    miRNAs;   

DOI  :  10.3390/ijms20040800

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown