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http://dx.doi.org/10.5352/JLS.2019.29.12.1305

Licochalcone C Induces Autophagy in Gefitinib-sensitive or-resistant Human Non-small Cell Lung Cancer Cells  

Oh, Ha-Na (Department of Pharmacy, College of Pharmacy, Mokpo National University)
Yoon, Goo (Department of Pharmacy, College of Pharmacy, Mokpo National University)
Chae, Jung-Il (Department of Dental Pharmacology, School of Dentistry, BK21 Plus, Jeonbuk National University)
Shim, Jung-Hyun (Department of Pharmacy, College of Pharmacy, Mokpo National University)
Publication Information
Journal of Life Science / v.29, no.12, 2019 , pp. 1305-1313 More about this Journal
Abstract
Licochalcone (LC), isolated from the roots of Glycyrrhiza inflata has multiple pharmacological effects including anti-inflammatory and anti-tumor activities. To date, Licochalcone C (LCC) has induced apoptosis and inhibited cell proliferation in oral and bladder cancer cells, but lung cancer has not yet been studied. In addition, no study reported LCC-induced autophagy in cancer until now. The present study was designed to investigate the effect of LCC on gefitinib-sensitive and -resistant lung cancer cells and elucidate the mechanism of its action. The 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay data showed that LCC significantly inhibited cell viability in non-small cell lung cancer (NSCLC) HCC827 (gefitinib-sensitive) and HCC827GR (gefitinib-resistant) cell lines. Interestingly, Annexin V/7-aminoactinomycin D double staining and cell cycle analysis showed an apoptosis rate within about 20% at the highest concentration of LCC. LCC induced G2/M arrest by reducing the expression of the cell cycle G2/M related proteins cyclin B1 and cdc2 in NSCLC cell lines. Treatment of LCC also induced autophagy by increasing the expression of the autophagy marker protein microtubule-associated protein 1 light chain 3 (LC3) and the protein autophagy-related gene 5 involved in the autophagy process. In addition, LCC increased the production of reactive oxygen species (ROS), and the cell viability was partially restored by treatment with the ROS inhibitor N-acetyl-L-cysteine. In western blotting analysis, the expression of cdc2 was increased and LC3 was decreased by the simultaneous treatment of NAC and LCC. These results indicate that LCC may contribute to anti-tumor effects by inducing ROS-dependent G2/M arrest and autophagy in NSCLC. In conclusion, LCC treatment may be useful as a potential therapeutic agent against NSCLC.
Keywords
Autophagy; Licochalcone C; non-small cell lung cancer; reactive oxygen species;
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1 Edinger, A. L. and Thompson, C. B. 2004. Death by design: Apoptosis, necrosis and autophagy. Curr. Opin. Cell Biol. 16, 663-669.   DOI
2 Engelman, J. A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J. O., Lindeman, N., Gale, C. M., Zhao, X., Christensen, J., Kosaka, T., Holmes, A. J., Rogers, A. M., Cappuzzo, F., Mok, T., Lee, C., Johnson, B. E., Cantley, L. C. and Janne, P. A. 2007. Met amplification leads to gefitinib resistance in lung cancer by activating erbb3 signaling. Science 316, 1039-1043.   DOI
3 Filomeni, G., De Zio, D. and Cecconi, F. 2015. Oxidative stress and autophagy: The clash between damage and metabolic needs. Cell Death Differ. 22, 377-388.   DOI
4 Fung, C., Chen, X., Grandis, J. R. and Duvvuri, U. 2012. Egfr tyrosine kinase inhibition induces autophagy in cancer cells. Cancer Biol. Ther. 13, 1417-1424.   DOI
5 Wang, P., Yuan, X., Wang, Y., Zhao, H., Sun, X. and Zheng, Q. 2015. Licochalcone c induces apoptosis via b-cell lymphoma 2 family proteins in t24 cells. Mol. Med. Rep. 12, 7623-7628.   DOI
6 Wang, R. C. and Levine, B. 2010. Autophagy in cellular growth control. FEBS Lett. 584, 1417-1426.   DOI
7 Zhang, X., Chen, L. X., Ouyang, L., Cheng, Y. and Liu, B. 2012. Plant natural compounds: Targeting pathways of autophagy as anti-cancer therapeutic agents. Cell Prolif. 45, 466-476.   DOI
8 Wei, Y., Zou, Z., Becker, N., Anderson, M., Sumpter, R., Xiao, G., Kinch, L., Koduru, P., Christudass, C. S., Veltri, R. W., Grishin, N. V., Peyton, M., Minna, J., Bhagat, G. and Levine, B. 2013. Egfr-mediated beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell 154, 1269-1284.   DOI
9 Westover, D., Zugazagoitia, J., Cho, B. C., Lovly, C. M. and Paz-Ares, L. 2018. Mechanisms of acquired resistance to first- and second-generation egfr tyrosine kinase inhibitors. Ann. Oncol. 29, i10-i19.
10 Yun, C. W. and Lee, S. H. 2018. The roles of autophagy in cancer. Int. J. Mol. Sci. 19, 3466.   DOI
11 Zheng, K., He, Z., Kitazato, K. and Wang, Y. 2019. Selective autophagy regulates cell cycle in cancer therapy. Theranostics 9, 104-125.   DOI
12 Furusawa, J., Funakoshi-Tago, M., Mashino, T., Tago, K., Inoue, H., Sonoda, Y. and Kasahara, T. 2009. Glycyrrhiza inflata-derived chalcones, licochalcone a, licochalcone b and licochalcone d, inhibit phosphorylation of nf-kappab p65 in lps signaling pathway. Int. Immunopharmacol. 9, 499-507.   DOI
13 Mathew, R., Karantza-Wadsworth, V. and White, E. 2007. Role of autophagy in cancer. Nat. Rev. Cancer 7, 961-967.   DOI
14 Gorzalczany, Y., Gilad, Y., Amihai, D., Hammel, I., Sagi-Eisenberg, R. and Merimsky, O. 2011. Combining an egfr directed tyrosine kinase inhibitor with autophagy-inducing drugs: A beneficial strategy to combat non-small cell lung cancer. Cancer Lett. 310, 207-215.   DOI
15 Jung, K. W., Won, Y. J., Oh, C. M., Kong, H. J., Lee, D. H. and Lee, K. H. 2017. Prediction of cancer incidence and mortality in Korea, 2017. Cancer Res. Treat. 49, 306-312.   DOI
16 Kim, Y. H., Shin, E. K., Kim, D. H., Lee, H. H., Park, J. H. and Kim, J. K. 2010. Antiangiogenic effect of licochalcone a. Biochem. Pharmacol. 80, 1152-1159.   DOI
17 Levine, B. 2007. Cell biology: Autophagy and cancer. Nature 446, 745-747.   DOI
18 Manu, K. A., Cao, P. H. A., Chai, T. F., Casey, P. J. and Wang, M. 2019. P21cip1/waf1 coordinates autophagy, proliferation and apoptosis in response to metabolic stress. Cancers 11, 1112.   DOI
19 Mathiassen, S. G., De Zio, D. and Cecconi, F. 2017. Autophagy and the cell cycle: A complex landscape. Front. Oncol. 7, 51.
20 Mizushima, N., Yoshimori, T. and Levine, B. 2010. Methods in mammalian autophagy research. Cell 140, 313-326.   DOI
21 Oh, H. N., Seo, J. H., Lee, M. H., Kim, C., Kim, E., Yoon, G., Cho, S. S., Cho, Y. S., Choi, H. W., Shim, J. H. and Chae, J. I. 2018. Licochalcone c induced apoptosis in human oral squamous cell carcinoma cells by regulation of the jak2/stat3 signaling pathway. J. Cell Biochem. 119, 10118-10130.   DOI
22 Scherz-Shouval, R. and Elazar, Z. 2011. Regulation of autophagy by ros: Physiology and pathology. Trends Biochem. Sci. 36, 30-38.   DOI
23 Trachootham, D., Alexandre, J. and Huang, P. 2009. Targeting cancer cells by ros-mediated mechanisms: A radical therapeutic approach? Nat. Rev. Drug Discov. 8, 579.   DOI
24 Shin, A., Oh, C. M., Kim, B. W., Woo, H., Won, Y. J. and Lee, J. S. 2017. Lung cancer epidemiology in Korea. Cancer Res. Treat. 49, 616-626.   DOI
25 Soria, J. C., Jang, S. J., Khuri, F. R., Hassan, K., Liu, D., Hong, W. K. and Mao, L. 2000. Overexpression of cyclin b1 in early-stage non-small cell lung cancer and its clinical implication. Cancer Res. 60, 4000-4004.
26 Thomas, A., Rajan, A. and Giaccone, G. 2012. Tyrosine kinase inhibitors in lung cancer. Hematol. Oncol. Clin. North Am. 26, 589-605, viii.   DOI
27 Thorburn, A., Thamm, D. H. and Gustafson, D. L. 2014. Autophagy and cancer therapy. Mol. Pharmacol. 85, 830-838.   DOI