Ethyl gallate suppresses proliferation and invasion in human breast cancer cells via Akt-NF-κB signaling

Cui,Hongxia; Yuan,Jiaxin; Du,Xiaohui; Wang,Ming; Yue,Liling; Liu,Jicheng

doi:10.3892/or.2014.3682

Ethyl gallate suppresses proliferation and invasion in human breast cancer cells via Akt-NF-κB signaling

Authors:
- Hongxia Cui
- Jiaxin Yuan
- Xiaohui Du
- Ming Wang
- Liling Yue
- Jicheng Liu
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Affiliations: Department of Clinical Pharmacology, Qiqihar Medical College, Qiqihar, Heilongjiang, P.R. China, Heilongjiang University of Chinese Medicine, Harbin 150040, P.R. China, Institute of Medicine, Qiqihar Medical College, Qiqihar, Heilongjiang 161042, P.R. China
Published online on: December 18, 2014 https://doi.org/10.3892/or.2014.3682
Pages: 1284-1290

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Abstract

Euphorbia fischeriana Steud is a traditional Chinese Medicine that is known to possess a variety of anticarcinogenic properties. However, the bioactive constituents in Euphorbia fischeriana Steud and molecular mechanisms underlying this action in cancer treatment remain poorly understood. The present study investigated the chemotherapy activity and molecular targets of Ethyl gallate, which is identified as the major constituent extracted from the roots of Euphorbia fischeriana Steud in breast cancer cell lines in vitro. The results showed Ethyl gallate obviously decreased cell proliferation in MDA-MB-231 and MCF-7 cells in a dose- and time-dependent manner. Highly invasive MDA-MB-231 cells were found to be highly sensitive to treatment. Furthermore, significantly decreased metastatic potential of highly metastatic MDA-MB‑231 cells by Ethyl gallate was identified via the inhibition of cell motility using invasion and migration through a polyethylene terephthalate membrane. Ethyl gallate treatment decreased the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9 by the downregulation of mRNA levels using RT-PCR, enzymes that are critical to tumor invasion. Treatment with Ethyl gallate decreased phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor-κB (NF-κB) activation in MDA-MB-231 cells. These results indicate that Ethyl gallate suppresses proliferation and invasion in human breast cancer cells by modulating the PI3K/Akt pathway, which may contribute to inhibiting their downstream targets such as NF-κB p-65, Bcl-2/Bax, and mRNA levels of MMP-2 and MMP-9 in breast cancer cells. Thus, the present study shed new light on Ethyl gallate, an important bioactive constituent of Euphorbia fischeriana Steud, in human breast cancer treatment. The findings may provide basal theories for wide therapeutic application in human breast cancer.

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1	Cleator S, Heller W and Coombes RC: Triple-negative breast cancer: therapeutic options. Lancet Oncol. 8:235–244. 2007. View Article : Google Scholar : PubMed/NCBI
2	van de Rijn M, Perou CM, Tibshirani R, et al: Expression of cytokeratins 17 and 5 identifies a group of breast carcinomas with poor clinical outcome. Am J Pathol. 161:1991–1996. 2002. View Article : Google Scholar : PubMed/NCBI
3	Foulkes WD, Brunet JS, Stefansson IM, et al: The prognostic implication of the basal-like (cyclin E^high/p27^low/p53⁺/glomeruloid-microvascular-proliferation⁺) phenotype of BRCA1-related breast cancer. Cancer Res. 64:830–835. 2004. View Article : Google Scholar : PubMed/NCBI
4	Folgueras AR, Pendás AM, Sánchez LM and López-Otín C: Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies. Int J Dev Biol. 48:411–424. 2004. View Article : Google Scholar : PubMed/NCBI
5	Lin YC, Tsai PH, Lin CY, Cheng CH, Lin TH, Lee KP, Huang KY, Chen SH, Hwang JJ, Kandaswami CC and Lee MT: Impact of flavonoids on matrix metalloproteinase secretion and invadopodia formation in highly invasive A431-III cancer cells. PLoS One. 8:e719032013. View Article : Google Scholar : PubMed/NCBI
6	Liu Y, Cao W, Zhang B, Liu YQ, Wang ZY, Wu YP, Yu XJ, Zhang XD, Ming PH, Zhou GB and Huang L: The natural compound magnolol inhibits invasion and exhibits potential in human breast cancer therapy. Sci Rep. 3:30982013.PubMed/NCBI
7	Ho YC, Yang SF, Peng CY, Chou MY and Chang YC: Epigallocatechin-3-gallate inhibits the invasion of human oral cancer cells and decreases the productions of matrix metalloproteinases and urokinase-plasminogen activator. J Oral Pathol Med. 36:588–593. 2007. View Article : Google Scholar : PubMed/NCBI
8	Lee WJ, Chen WK, Wang CJ, Lin WL and Tseng TH: Apigenin inhibits HGF-promoted invasive growth and metastasis involving blocking PI3K/Akt pathway and β4 integrin function in MDA-MB-231 breast cancer cells. Toxicol Appl Pharmacol. 226:178–191. 2008. View Article : Google Scholar
9	Qin GW and Xu RS: Recent advances on bioactive natural products from Chinese medicinal plants. Med Res Rev. 18:375–382. 1998. View Article : Google Scholar : PubMed/NCBI
10	Wang YB, Huang R, Wang HB, Jin HZ, Lou LG and Qin GW: Diterpenoids from the roots of Euphorbia fischeriana. J Nat Prod. 69:967–970. 2006. View Article : Google Scholar : PubMed/NCBI
11	Shi HM, Williams ID, Sung HH, Zhu HX, Ip NY and Min ZD: Cytotoxic diterpenoids from the roots of Euphorbia ebracteolata. Planta Med. 71:349–354. 2005. View Article : Google Scholar : PubMed/NCBI
12	Wang JH, Zhang K, Niu HY, Shu LH, Yue DM, Li D and He P: Jolkinolide B from Euphorbia fischeriana Steud induces in human leukemic cells apoptosis via JAK2/STAT3 pathways. Int J Clin Pharmacol Ther. 51:170–178. 2013. View Article : Google Scholar
13	Yan SS, Li Y, Wang Y, Shen SS, Gu Y, Wang HB, Qin GW and Yu Q: 17- Acetoxyjolkinolide B irreversibly inhibits IκB kinase and induces apoptosis of tumor cells. Mol Cancer Ther. 7:1523–1532. 2008. View Article : Google Scholar : PubMed/NCBI
14	Wang JH, Zhou YJ, Bai X and He P: Jolkinolide B from Euphorbia fischeriana Steud induces apoptosis in human leukemic U937 cells through PI3K/Akt and XIAP pathways. Mol Cells. 32:451–457. 2011. View Article : Google Scholar : PubMed/NCBI
15	Wang Y, Ma X, Yan S, Shen S, Zhu H, Gu Y, Wang H, Qin G and Yu Q: 17-Hydroxy-jolkinolide B inhibits signal transducers and activators of transcription 3 signaling by covalently cross-linking Janus kinases and induces apoptosis of human cancer cells. Cancer Res. 69:7302–7310. 2009. View Article : Google Scholar : PubMed/NCBI
16	Chaffer CL and Weinberg RA: A perspective on cancer cell metastasis. Science. 331:1559–1564. 2011. View Article : Google Scholar : PubMed/NCBI
17	Hung SH, Shen KH, Wu CH, Liu CL and Shih YW: α-Mangostin suppresses PC-3 human prostate carcinoma cell metastasis by inhibiting matrix metalloproteinase-2/9 and urokinase-plasminogen expression through the JNK signaling pathway. J Agric Food Chem. 57:1291–1298. 2009. View Article : Google Scholar : PubMed/NCBI
18	Chen PN, Chu SC, Chiou HL, Kuo WH, Chiang CL and Hsieh YS: Mulberry anthocyanins, cyanidin 3-rutinoside and cyanidin 3-glucoside, exhibited an inhibitory effect on the migration and invasion of a human lung cancer cell line. Cancer Lett. 235:248–259. 2006. View Article : Google Scholar
19	Azios NG and Dharmawardhane SF: Resveratrol and estradiol exert disparate effects on cell migration, cell surface actin structures, and focal adhesion assembly in MDA-MB-231 human breast cancer cells. Neoplasia. 7:128–140. 2005. View Article : Google Scholar : PubMed/NCBI
20	Kessenbrock K, Plaks V and Werb Z: Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 141:52–67. 2010. View Article : Google Scholar : PubMed/NCBI
21	Das R, Philip S, Mahabeleshwar GH, Bulbule A and Kundu GC: Osteopontin: it’s role in regulation of cell motility and nuclear factor κB-mediated urokinase type plasminogen activator expression. IUBMB Life. 57:441–447. 2005. View Article : Google Scholar : PubMed/NCBI
22	Lu KW, Tsai ML, Chen JC, Hsu SC, Hsia TC, Lin MW, Huang AC, Chang YH, Ip SW, Lu HF and Chung JG: Gypenosides inhibited invasion and migration of human tongue cancer SCC4 cells through down-regulation of NFκB and matrix metalloproteinase-9. Anticancer Res. 28:1093–1099. 2008.PubMed/NCBI
23	Park SY, Kim JH, Lee YJ, Lee SJ and Kim Y: Surfactin suppresses TPA-induced breast cancer cell invasion through the inhibition of MMP-9 expression. Int J Oncol. 42:287–296. 2013.
24	Hojilla CV, Mohammed FF and Khokha R: Matrix metalloproteinases and their tissue inhibitors direct cell fate during cancer development. Br J Cancer. 89:1817–1821. 2003. View Article : Google Scholar : PubMed/NCBI
25	Kim Y, Kang H, Jang SW and Ko J: Celastrol inhibits breast cancer cell invasion via suppression of NF-κB-mediated matrix metalloproteinase-9 expression. Cell Physiol Biochem. 28:175–184. 2011. View Article : Google Scholar
26	Rangaswami H, Bulbule A and Kundu GC: Nuclear factor-inducing kinase plays a crucial role in osteopontin-induced MAPK/IκBα kinase-dependent nuclear factor κB-mediated promatrix metalloproteinase-9 activation. J Biol Chem. 279:38921–38935. 2004. View Article : Google Scholar : PubMed/NCBI
27	Yamaguchi N, Ito T, Azuma S, Ito E, Honma R, Yanagisawa Y, Nishikawa A, Kawamura M, Imai J, Watanabe S, Semba K and Inoue J: Constitutive activation of nuclear factor-κB is preferentially involved in the proliferation of basal-like subtype breast cancer cell lines. Cancer Sci. 100:1668–1674. 2009. View Article : Google Scholar : PubMed/NCBI
28	Kang H, Lee M, Choi KC, Shin DM, Ko J and Jang SW: N-(4-hydroxyphenyl)retinamide inhibits breast cancer cell invasion through suppressing NF-KB activation and inhibiting matrix metalloproteinase-9 expression. J Cell Biochem. 113:2845–2855. 2012. View Article : Google Scholar : PubMed/NCBI
29	Thangapazham RL, Passi N and Maheshwari RK: Green tea polyphenol and epigallocatechin gallate induce apoptosis and inhibit invasion in human breast cancer cells. Cancer Biol Ther. 6:1938–1943. 2007. View Article : Google Scholar : PubMed/NCBI
30	Viatour P, Bentires-Alj M, Chariot A, Deregowski V, de Leval L, Merville MP and Bours V: NF-κB2/p100 induces Bcl-2 expression. Leukemia. 17:1349–1356. 2003. View Article : Google Scholar : PubMed/NCBI
31	Marsden VS, O’Connor L, O’Reilly LA, Silke J, Metcalf D, Ekert PG, Huang DC, Cecconi F, Kuida K, Tomaselli KJ, Roy S, Nicholson DW, Vaux DL, Bouillet P, Adams JM and Strasser A: Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome. Nature. 419:634–637. 2002. View Article : Google Scholar : PubMed/NCBI
32	Emi M, Kim R, Tanabe K, Uchida Y and Toge T: Targeted therapy against Bcl-2-related proteins in breast cancer cells. Breast Cancer Res. 7:940–952. 2005. View Article : Google Scholar
33	Patel JB, Mehta J, Belosay A, Sabnis G, Khandelwal A, Brodie AM, Soprano DR and Njar VC: Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth. Br J Cancer. 96:1204–1215. 2007. View Article : Google Scholar : PubMed/NCBI
34	Aggarwal BB: Nuclear factor-κB: the enemy within. Cancer Cell. 6:203–208. 2004. View Article : Google Scholar : PubMed/NCBI