Issue
Esculetin inhibits the proliferation of human lung cancer cells by targeting epithelial-to-mesenchymal transition of the cells
Corresponding Author(s) : Zhong Han
Cellular and Molecular Biology,
Vol. 65 No. 7: Issue 7
Abstract
Lung cancer is characterized by high mortality and it is a serious threat to human health. At present, strategies used for treatment of lung cancer are not effective. Hence, there is need for new drugs that can effectively treat the metastatic stage of the cancer. The present study investigated the effect of esculetin on proliferation and epithelial-mesenchymal transition (EMT) of human lung cancer (A549) cells, and the underlying mechanism.Cell proliferation was assessed using MTT assay. Real-time quantitative polymerase chain reaction (qRT-PCR) and Western blotting were employed for the determination of changes in the expression levels of vimentin, Snail and E-cadherin mRNAs. Cell invasion and migration were determined using Transwell assay. The results showed that esculetin significantly and time- and dose-dependently inhibited the proliferation of A549 cells (p < 0.05). It also significantly and dose-dependently reduced their invasive ability (p < 0.05). The levels of expression of vimentin and Snail mRNAs were significantly and dose-dependently down-regulated in esculetin-treated A549 cells, when compared with the control cells (p < 0.05). Esculetin treatment significantly and dose-dependently upregulated the expression of E-cadherin mRNA (p < 0.05). These results demonstrate that esculetin effectively inhibits the proliferation of A549 cells, and regulates EMT of the cells via the down-regulation of vimentin and Snail, and up-regulation of E-cadherin expressions.
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- Yarmus L, Nguyen PT, Montemayor K, Jennings M, Bade B, Shafiq M, et al. Year in review 2017: Interventional pulmonology, lung cancer, pleural disease and respiratory infections. J Regulation 2018; 23: 628-635.
- Vestergaard HH, Christensen MR, Lassen UN. A systematic review of targeted agents for non-small cell lung cancer. J Audiol Otol 2018; 57: 176-186.
- Gouvinhas C, DeMello RA, Oliveira D, Castro-Lopes JM, Castelo-Branco P, dos Santos RS, et al. Lung cancer: a brief review of epidemiology and screening. J Field Ornithol 2018; 14: 567-575.
- Popat S, Mok T, Yang JCH, Wu YL, Lungershausen J, Stammberger U, et al. Afatinib in the treatment of EGFR mutation-positive NSCLC–a network meta-analysis. Lung Cancer 2014; 85: 230-238.
- Lv XQ, Qiao XR, Su L, Chen SZ. Honokiol inhibits EMT-mediated motility and migration of human non-small cell lung cancer cells in vitro by targeting c-FLIP. J Appl Pharm Sci 2016; 37: 1574.
- Li W, Wang Q, Su Q, Ma D, An C, Ma L, et al. Cells: Honokiol suppresses renal cancer cells metastasis via dual-blocking epithelial-mesenchymal transition and cancer stem cell properties through modulating miR-141/ZEB2 signaling. Mol Cells 2014; 37: 383.
- Liu R, Sun Q, Sun A, Cui J. Isolation and purification of coumarin compounds from Cortex fraxinus by high-speed counter-current chromatography. J Chromatogr 2005; 1072: 195-199.
- Watanabe K, Ito A, Sato T, Saito T, Hayashi H, Niitani Y. Esculetin suppresses proteoglycan metabolism by inhibiting the production of matrix metalloproteinases in rabbit chondrocytes. Eur J Pharmacol 1999; 370: 297-305.
- Martín-Aragón S, Benedí JM, Villar AM. Effects of the antioxidant esculetin (6, 7-dihydroxycoumarin) on the glutathione system and lipid peroxidation in mice. Gerontol 1998; 44: 21-25.
- Hu Y, Chen X, Duan H, Hu Y, Mu X. Immunotoxicology: Chinese herbal medicinal ingredients inhibit secretion of IL-6, IL-8, E-selectin and TXB2 in LPS-induced rat intestinal microvascular endothelial cells. Immunopharmacol Immunotoxicol 2009; 31: 550-555.
- Duncan SH, Leitch ECM, Stanley KN, Richardson AJ, Laven RA, Flint HJ, et al. Effects of esculin and esculetin on the survival of Escherichia coli O157 in human faecal slurries, continuous-flow simulations of the rumen and colon and in calves. Br J Nutr 2004; 91:749-755.
- Kawaii S, Tomono Y, Ogawa K, Sugiura M, Yano M, Yoshizawa Y, et al. Antiproliferative effect of isopentenylated coumarins on several cancer cell lines. Anticancer Res 2001; 21: 1905-1911.
- Nagasaka M, Kukreja G, Abdulfatah E, Vaishampayan U, Sukari A. Role of molecular profiling in diagnosis of papillary renal-cell cancer presenting as cancer of unknown primary site. Japanese Classification Gastric Carcinoma 2017; 15: 713-717.
- Wang CJ, Hsieh YJ, Chu CY, Lin YL, Tseng TH. Inhibition of cell cycle progression in human leukemia HL-60 cells by esculetin. Cancer Lett 2002; 183:163-168.
- Yue D, Li H, Che J, Zhang Y, Tseng HHK, Jin JQ, et al. Hedgehog/Gli promotes epithelial-mesenchymal transition in lung squamous cell carcinomas. J Exp Clin Cancer Res 2014; 33: 34.
- You J, Li Y, Fang N, Liu B, Zu L, Chang R, et al. MiR-132 suppresses the migration and invasion of lung cancer cells via targeting the EMT regulator ZEB2. Plos One 2014; 9: 91827.
- Chu CY, Tsai YY, Wang CJ, Lin WL, Tseng TH. Induction of apoptosis by esculetin in human leukemia cells. Eur J Pharmacol 2001; 416: 25-32.
- Piscopo P, Rivabene R, Adduci A, Mallozzi C, Malvezzi-Campeggi L, Crestini A, et al. Hypoxia induces up-regulation of progranulin in neuroblastoma cell lines. J Neuroinflamm 2010; 57: 893-898.
- Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol 2014; 15: 178.
- Yilmaz M, Christofori G. Mechanisms of motility in metastasizing cells. Mol Cancer Res 2010; 8: 629-642.
- McInroy L, Määttä A. Down-regulation of vimentin expression inhibits carcinoma cell migration and adhesion. Biochem Biophys Res Commum 2007; 360: 109-114.
References
Yarmus L, Nguyen PT, Montemayor K, Jennings M, Bade B, Shafiq M, et al. Year in review 2017: Interventional pulmonology, lung cancer, pleural disease and respiratory infections. J Regulation 2018; 23: 628-635.
Vestergaard HH, Christensen MR, Lassen UN. A systematic review of targeted agents for non-small cell lung cancer. J Audiol Otol 2018; 57: 176-186.
Gouvinhas C, DeMello RA, Oliveira D, Castro-Lopes JM, Castelo-Branco P, dos Santos RS, et al. Lung cancer: a brief review of epidemiology and screening. J Field Ornithol 2018; 14: 567-575.
Popat S, Mok T, Yang JCH, Wu YL, Lungershausen J, Stammberger U, et al. Afatinib in the treatment of EGFR mutation-positive NSCLC–a network meta-analysis. Lung Cancer 2014; 85: 230-238.
Lv XQ, Qiao XR, Su L, Chen SZ. Honokiol inhibits EMT-mediated motility and migration of human non-small cell lung cancer cells in vitro by targeting c-FLIP. J Appl Pharm Sci 2016; 37: 1574.
Li W, Wang Q, Su Q, Ma D, An C, Ma L, et al. Cells: Honokiol suppresses renal cancer cells metastasis via dual-blocking epithelial-mesenchymal transition and cancer stem cell properties through modulating miR-141/ZEB2 signaling. Mol Cells 2014; 37: 383.
Liu R, Sun Q, Sun A, Cui J. Isolation and purification of coumarin compounds from Cortex fraxinus by high-speed counter-current chromatography. J Chromatogr 2005; 1072: 195-199.
Watanabe K, Ito A, Sato T, Saito T, Hayashi H, Niitani Y. Esculetin suppresses proteoglycan metabolism by inhibiting the production of matrix metalloproteinases in rabbit chondrocytes. Eur J Pharmacol 1999; 370: 297-305.
Martín-Aragón S, Benedí JM, Villar AM. Effects of the antioxidant esculetin (6, 7-dihydroxycoumarin) on the glutathione system and lipid peroxidation in mice. Gerontol 1998; 44: 21-25.
Hu Y, Chen X, Duan H, Hu Y, Mu X. Immunotoxicology: Chinese herbal medicinal ingredients inhibit secretion of IL-6, IL-8, E-selectin and TXB2 in LPS-induced rat intestinal microvascular endothelial cells. Immunopharmacol Immunotoxicol 2009; 31: 550-555.
Duncan SH, Leitch ECM, Stanley KN, Richardson AJ, Laven RA, Flint HJ, et al. Effects of esculin and esculetin on the survival of Escherichia coli O157 in human faecal slurries, continuous-flow simulations of the rumen and colon and in calves. Br J Nutr 2004; 91:749-755.
Kawaii S, Tomono Y, Ogawa K, Sugiura M, Yano M, Yoshizawa Y, et al. Antiproliferative effect of isopentenylated coumarins on several cancer cell lines. Anticancer Res 2001; 21: 1905-1911.
Nagasaka M, Kukreja G, Abdulfatah E, Vaishampayan U, Sukari A. Role of molecular profiling in diagnosis of papillary renal-cell cancer presenting as cancer of unknown primary site. Japanese Classification Gastric Carcinoma 2017; 15: 713-717.
Wang CJ, Hsieh YJ, Chu CY, Lin YL, Tseng TH. Inhibition of cell cycle progression in human leukemia HL-60 cells by esculetin. Cancer Lett 2002; 183:163-168.
Yue D, Li H, Che J, Zhang Y, Tseng HHK, Jin JQ, et al. Hedgehog/Gli promotes epithelial-mesenchymal transition in lung squamous cell carcinomas. J Exp Clin Cancer Res 2014; 33: 34.
You J, Li Y, Fang N, Liu B, Zu L, Chang R, et al. MiR-132 suppresses the migration and invasion of lung cancer cells via targeting the EMT regulator ZEB2. Plos One 2014; 9: 91827.
Chu CY, Tsai YY, Wang CJ, Lin WL, Tseng TH. Induction of apoptosis by esculetin in human leukemia cells. Eur J Pharmacol 2001; 416: 25-32.
Piscopo P, Rivabene R, Adduci A, Mallozzi C, Malvezzi-Campeggi L, Crestini A, et al. Hypoxia induces up-regulation of progranulin in neuroblastoma cell lines. J Neuroinflamm 2010; 57: 893-898.
Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol 2014; 15: 178.
Yilmaz M, Christofori G. Mechanisms of motility in metastasizing cells. Mol Cancer Res 2010; 8: 629-642.
McInroy L, Määttä A. Down-regulation of vimentin expression inhibits carcinoma cell migration and adhesion. Biochem Biophys Res Commum 2007; 360: 109-114.