Morusin suppresses A549 cell migration and induces cell apoptosis by downregulating the expression of COX‑2 and VEGF genes

Yin,Xiao‑Lu; Lv,Yi; Wang,Shu; Zhang,Yu‑Qing

doi:10.3892/or.2018.6431

Morusin suppresses A549 cell migration and induces cell apoptosis by downregulating the expression of COX‑2 and VEGF genes

Authors:
- Xiao‑Lu Yin
- Yi Lv
- Shu Wang
- Yu‑Qing Zhang
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Affiliations: Silk Biotechnology Laboratory, School of Basic Medical and Biological Sciences, Soochow University, Suzhou, Jiangsu 215123, P.R. China
Published online on: May 9, 2018 https://doi.org/10.3892/or.2018.6431
Pages: 504-510

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Abstract

The present study aimed to examine the inhibitory effects of morusin on the human lung cancer cell line A549. Various doses of morusin were applied to A549 cells and the effects were assessed by wound‑healing and MTT assays, flow cytometry analysis of apoptosis, a mitochondrial membrane potential assay and RT‑PCR. The results indicated that the concentrations of 10 and 30 µg/ml morusin significantly inhibited A549 cells and signs of apoptosis were observed. In addition, the wound‑healing assay results revealed that morusin inhibited cell migration. Flow cytometry analysis demonstrated that the rates of apoptosis were 16.46, 55.80 and 70.80% following treatment with 1, 10 and 30 µg/ml of morusin, respectively, and that the mitochondrial membrane potentials also decreased with the increase of morusin. Furthermore, morusin increased the antioxidant activities of the A549 cells. RT‑PCR analysis revealed that the expression levels of COX‑2 and VEGF were downregulated following morusin treatment. In conclusion, morusin significantly inhibited the proliferation of the lung cancer cell line A549, and may have affected the invasion and migration of the cells by downregulating the expression of tumor angiogenesis‑related genes.

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1	Parkin DM, Bray F, Ferlay J and Pisani P: Estimating the world cancer burden: Globocan 2000. Int J Cancer. 94:153–156. 2001. View Article : Google Scholar : PubMed/NCBI
2	Beadsmoore CJ and Screaton NJ: Classification, staging and prognosis of lung cancer. Eur J Radiol. 45:8–17. 2003. View Article : Google Scholar : PubMed/NCBI
3	Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 55:742005. View Article : Google Scholar : PubMed/NCBI
4	Kim SY, Gao JJ, Lee WC, Ryu KS, Lee KR and Kim YC: Antioxidative flavonoids from the leaves of Morus alba. Arch Pharm Res. 22:81–85. 1999. View Article : Google Scholar : PubMed/NCBI
5	Asano N, Yamashita T, Yasuda K, Ikeda K, Kizu H, Kameda Y, Kato A, Nash RJ, Lee HS and Ryu KS: Polyhydroxylated alkaloids isolated from mulberry trees (Morus alba L.) and silkworms (Bombyx mori L). J Agric Food Chem. 49:4208–4213. 2001. View Article : Google Scholar : PubMed/NCBI
6	Oh H, Ko EK, Jun JY, Oh MH, Park SU, Kang KH, Lee HS and Kim YC: Hepatoprotective and free radical scavenging activities of prenylflavonoids, coumarin, and stilbene from Morus alba. Planta Med. 68:932–934. 2002. View Article : Google Scholar : PubMed/NCBI
7	Qiu F, Komatsu K, Kawasaki K, Saito K, Yao XS and Kano Y: A novel stilbene glucoside, oxyresveratrol 3′-O-β-glucopyranoside, from the root bark of Morus alba. Planta Med. 62:559–561. 1996. View Article : Google Scholar : PubMed/NCBI
8	Piao SJ, Qiu F, Chen LX, Pan Y and Dou DQ: New stilbene, benzofuran, and coumarin glycosides from Morus alba. Helvetica Chimica Acta. 92:579–587. 2009. View Article : Google Scholar
9	Piao SJ, Chen LX, Kang N and Qiu F: Simultaneous determination of five characteristic stilbene glycosides in root bark of Morus alba L. (Cortex mori) using high-performance liquid chromatography. Phytochem Anal. 22:230–235. 2011. View Article : Google Scholar : PubMed/NCBI
10	Nomura T, Fukai T, Yamada S and Katayanagi M: Studies on the constituents of the cultivated mulberry tree. I. Three new phenylflavones from the root bark of Morus alba L. Chem Pharm Bul. 26:1394–1402. 1978. View Article : Google Scholar
11	Ferlinahayati, Syah YM, Juliawaty LD, Achmad SA, Hakim EH, Takayama H, Said IM and Latip J: Phenolic constituents from the wood of Morus australis with cytotoxic activity. Z Naturforsch C. 63:35–39. 2008. View Article : Google Scholar : PubMed/NCBI
12	Suhartati T, Yandri AS, Hadi S and Jhons FS: Morusin, a Bioactive Compound from the Root Bark of Artocarpus dadah. Eur J Sci Res. 38:643–648. 2009.
13	Mazimba O, Majinda RRT and Motlhanka D: Antioxidant and antibacterial constituents from Morus nigra. Afc J Pharm Pharmaco. 5:751–754. 2011.
14	Guptaa G, Duaa K, Kazmi I and Anwar F: Anticonvulsant activity of Morusin isolated from Morus alba: Modulation of GABA receptor. Biomed Aging Pathology. 4:29–32. 2014. View Article : Google Scholar
15	Luo SD, Nemec J and Ning BM: Anti-HIV flavonoids from Morus alba. Acta Botanica Yunnanica. 17:89–95. 1995.
16	Cho JK, Ryu YB, Curtis-Long MJ, Kim JY, Kim D, Lee S, Lee WS and Park KH: Inhibition and structural reliability of prenylated flavones from the stem bark of Morus lhou on b-secretase (BACE-1). Bioorg Med Chem Lett. 21:2945–2948. 2011. View Article : Google Scholar : PubMed/NCBI
17	Kim JY, Lee WS, Kim YS, Curtis-Long MJ, Lee BW, Ryu YB and Park KH: Isolation of cholinesterase-inhibiting flavonoids from Morus lhou. J Agr Food Chem. 59:4589–4596. 2011. View Article : Google Scholar
18	Yoshizawa S, Suganuma M, Fujiki H, Fukai T, Nomura T and Sugimura T: Morusin, isolated from root bark of Morus alba L., inhibits tumour promotion of teleocidin. Phytotherapy Res. 3:193–195. 1989. View Article : Google Scholar
19	Fujiki H, Suganuma M, Takagi K, Yoshizawa S, Furuya HS, Yoshizawa S, Nishiwaki S, Kobayashi M, Okuda T, Nomura T, et al: Sarcophytols A and B, (−)-epigallocatechin gallate (EGCG), and morusin, anticarcinogenesis radiation Protection. 2:357–362. 1991.
20	Wang F, Zhang D, Mao J, Ke XX, Zhang R, Yin C, Gao N and Cui H: Morusin inhibits cell proliferation and tumor growth by down-regulating c-Myc in human gastric cancer. Oncotarget. 8:57187–57200. 2017.PubMed/NCBI
21	Zhao JL: Morusin induces human colorectal cancer cell death via apoptosisNational Cheng Kung University; 2003
22	Lee JC, Won SJ, Chao CL, Wu FL, Liu HS, Ling P, Lin CN and Su CL: Morusin induces apoptosis and suppresses NF-κB activity in human colorectal cancer HT-29 cells. Biochem Biophys Res Commun. 372:236–242. 2008. View Article : Google Scholar : PubMed/NCBI
23	Lin WL, Lai DY, Lee YJ, Chen NF and Tseng TH: Antitumor progression potential of morusin suppressing STAT3 and NFκB in human hepatoma SK-Hep1 cells. Toxicol Lett. 232:490–498. 2015. View Article : Google Scholar : PubMed/NCBI
24	Kim C, Kim JH, Oh EY, Nam D, Lee SG, Lee J, Kim SH, Shim BS and Ahn KS: Blockage of STAT3 signaling pathway by morusin induces apoptosis and inhibits invasion in human pancreatic tumor cells. Pancreas. 45:409–419. 2016. View Article : Google Scholar : PubMed/NCBI
25	Wang L, Guo H, Yang L, Dong L, Lin C, Zhang J, Lin P and Wan X: Morusin inhibits human cervical cancer stem cell growth and migration through attenuation of NF-κB activity and apoptosis induction. Mol Cell Biochem. 379:7–18. 2013. View Article : Google Scholar : PubMed/NCBI
26	Wan LZ, Ma B and Zhang YQ: Preparation of morusin from Ramulus mori and its effects on mice with transplanted H22 hepatocarcinoma. Biofactors. 40:636–645. 2014. View Article : Google Scholar : PubMed/NCBI
27	Ding B, Lv Y and Zhang YQ: Anti-tumor effect of morusin from the branch bark of cultivated mulberry in Bel-7402 cells via the MAPK pathway. Rsc Adv. 6:17396–17404. 2016. View Article : Google Scholar
28	Mosmann T: Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Medthods. 65:55–63. 1983. View Article : Google Scholar
29	Petit PX, Susin SA, Zamzami N, Mignotte B and Kroemer G: Mitochondria and programmed cell death: Back to the future. FEBS Lett. 396:7–13. 1996. View Article : Google Scholar : PubMed/NCBI
30	Prager GW, Lackner EM, Krauth MT, Unseld M, Poettler M, Laffer S, Cerny-Reiterer S, Lamm W, Kornek GV, Binder BR, et al: Targeting of VEGF-dependent transendothelial migration of cancer cells by bevacizumab. Mol Oncol. 4:150–160. 2010. View Article : Google Scholar : PubMed/NCBI
31	Gong C, Xu C, Ji L and Wang Z: A novel semi-synthetic andrographolide analogue A5 inhibits tumor angiogenesis via blocking the VEGFR2-p38/ERK1/2 signal pathway. Biosci Trends. 7:230–236. 2013.PubMed/NCBI
32	Chen LH, Fang J, Li H, Demark-Wahnefried W and Lin X: Enterolactone induces apoptosis in human prostate carcinoma LNCaP cells via a mitochondrial-mediated, caspase-dependent pathway. Mol Cancer Ther. 6:2581–2590. 2007. View Article : Google Scholar : PubMed/NCBI
33	Chen M, Guerrero AD, Huang L, Shabier Z, Pan M, Tan TH and Wang J: Caspase-9-induced mitochondrial disruption through cleavage of anti-apoptotic BCL-2 family members. J Biol Chem. 282:33888–33895. 2007. View Article : Google Scholar : PubMed/NCBI
34	Sikora J: Tumor angiogenesis in human lung adenocarcinoma. Cancer. 76:915–916. 1995. View Article : Google Scholar : PubMed/NCBI
35	Kim TJ, Lee YS, Kang JH, Kim YS and Kang CS: Prognostic significance of expression of VEGF and Cox-2 in nasopharyngeal carcinoma and its association with expression of C-erbB2 and EGFR. J Surg Oncol. 103:46–52. 2011. View Article : Google Scholar : PubMed/NCBI
36	Rundhaug JE, Mikulec C, Pavone A and Fischer SM: A role for cyclooxygenase-2 in ultraviolet light-induced skin carcinogenesis. Mol Carcinog. 46:692–698. 2007. View Article : Google Scholar : PubMed/NCBI
37	Cao Y and Prescott SM: Many actions of cyclooxygenase-2 in cellular dynamics and in cancer. J Cell Physiol. 190:279–286. 2002. View Article : Google Scholar : PubMed/NCBI
38	Bremnes RM, Camps C and Sirera R: Angiogenesis in non-small cell lung cancer: The prognostic impact of neoangiogenesis and the cytokines VEGF and bFGF in tumours and blood. Lung Cancer. 51:143–158. 2006. View Article : Google Scholar : PubMed/NCBI
39	Ferrara N and Kerbel RS: Angiogenesis as a therapeutic target. Nature. 438:967–974. 2005. View Article : Google Scholar : PubMed/NCBI
40	Izuta H, Shimazawa M, Tsuruma K, Araki Y, Mishima S and Hara H: Bee products prevent VEGF-induced angiogenesis in human umbilical vein endothelial cells. BMC Complement Altern Med. 9:452009. View Article : Google Scholar : PubMed/NCBI