Emodin inhibits epithelial‑mesenchymal transition and metastasis of triple negative breast cancer via antagonism of CC‑chemokine ligand 5 secreted from adipocytes

Song,Xiaoyun; Zhou,Xiqiu; Qin,Yuenong; Yang,Jianfeng; Wang,Yu; Sun,Zhenping; Yu,Kui; Zhang,Shuai; Liu,Sheng

doi:10.3892/ijmm.2018.3638

Emodin inhibits epithelial‑mesenchymal transition and metastasis of triple negative breast cancer via antagonism of CC‑chemokine ligand 5 secreted from adipocytes

Authors:
- Xiaoyun Song
- Xiqiu Zhou
- Yuenong Qin
- Jianfeng Yang
- Yu Wang
- Zhenping Sun
- Kui Yu
- Shuai Zhang
- Sheng Liu
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Affiliations: Department of General Surgery, Pudong Branch of Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China, Department of General Surgery and Pharmacology Laboratory of Traditional Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, P.R. China
Published online on: April 23, 2018 https://doi.org/10.3892/ijmm.2018.3638
Pages: 579-588

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Abstract

Triple negative breast cancer (TNBC) has the lowest survival rate of the breast cancer subtypes owing to its aggressive and metastatic behavior. It has been reported that peritumoral adipose tissue contributes to the cell invasiveness and dissemination of TNBC. Emodin is an active anthraquinone derivative isolated from Rheum palmatum, with anticancer properties that have been reported to inhibit lung metastasis in a nude mouse xenograft model. In the present study, the effects of emodin on human TNBC cells and adipocytes were investigated in vivo and in vitro. The TNBC cell lines MDA‑MB‑231 and MDA‑MB‑453 were co‑cultured with human adipocytes and treated with either emodin or epirubicin. Cell proliferation was assessed by MTT assay and migration and invasion were examined using a wound healing assay and a Transwell assay. interleukin‑8, CC‑chemokine ligand 5 (CCL5) and insulin‑like growth factor‑1 levels in the culture supernatants were detected by ELISA. The epithelial‑mesenchymal transition (EMT) or metastasis associated markers were determined by western blot analysis. Nude mice fed with a high fat and sugar diet were used investigate the in vivo effect of emodin. The results showed that emodin inhibited TNBC proliferation and invasion more efficiently than epirubicin when co‑cultured with adipocytes by downregulating the level of CCL5 in adipocyte supernatants; inhibiting the expression level of protein kinase B (AKT); and activating glycogen synthase kinase‑3i (GSK3) and β‑catenin. This led to the suppressed expression of EMT‑ and invasion‑associated markers, including vimentin, snail, matrix metalloproteinase (MMP)‑2 and MMP‑9, and upregulation of E‑cadherin, contributing to the inhibition of invasion. The in vivo assay showed that emodin inhibited tumor growth, and suppressed the lung and liver metastasis of TNBC cells by decreasing the secretion of CCL5 in mice fed a high fat and sugar diet more efficiently when compared with epirubicin. In conclusion, emodin inhibited the secretion of CCL5 from adipocytes, inhibited the EMT of TNBC cells, and inhibited tumor growth and lung and liver metastasis, which indicated a novel role of emodin in preventing the metastasis of TNBC.

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1	Siegel RL, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
2	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI
3	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
4	Brenton JD, Carey LA, Ahmed AA and Caldas C: Molecular classification and molecular forecasting of breast cancer: Ready for clinical application? J Clin Oncol. 23:7350–7360. 2005. View Article : Google Scholar : PubMed/NCBI
5	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
6	Foulkes WD, Smith IE and Reisfilho JS: Triple-negative breast cancer. N Engl J Med. 363:1938–1948. 2010. View Article : Google Scholar : PubMed/NCBI
7	Calle EE and Kaaks R: Overweight, obesity and cancer: Epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 4:579–591. 2004. View Article : Google Scholar : PubMed/NCBI
8	Nieman K, Romero IL, Van Houten B and Lengyel E: Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochim Biophys Acta. 1831:1533–1541. 2013. View Article : Google Scholar : PubMed/NCBI
9	Bifulco M and Pisanti S: ‘Adiponcosis’: A new term to name the obesity and cancer link. J Clin Endocrinol Metab. 98:4664–4665. 2013. View Article : Google Scholar : PubMed/NCBI
10	Iyengar P, Combs TP, Shah SJ, Gouon-Evans V, Pollard JW, Albanese C, Flanagan L, Tenniswood MP, Guha C, Lisanti MP, et al: Adipocyte-secreted factors synergistically promote mammary tumorigenesis through induction of anti-apoptotic transcriptional programs and proto-oncogene stabilization. Oncogene. 22:6408–6423. 2003. View Article : Google Scholar : PubMed/NCBI
11	Park J, Morley TS, Kim M, Clegg DJ and Scherer PE: Obesity and cancer-mechanisms underlying tumour progression and recurrence. Nat Rev Endocrinol. 10:455–465. 2014. View Article : Google Scholar : PubMed/NCBI
12	D’Esposito V, Passaretti F, Hammarstedt A, Liguoro D, Terracciano D, Molea G, Canta L, Miele C, Smith U, Beguinot F and Formisano P: Adipocyte-released insulin-like growth factor-1 is regulated by glucose and fatty acids and controls breast cancer cell growth in vitro. Diabetologia. 55:2811–2822. 2012. View Article : Google Scholar :
13	Luboshits G, Shina S, Kaplan O, Engelberg S, Nass D, Lifshitz-Mercer B, Chaitchik S, Keydar I and Ben-Baruch A: Elevated expression of the CC chemokine regulated on activation, normal T cell expressed and secreted (RANTES) in advanced breast carcinoma. Cancer Res. 59:4681–4687. 1999.PubMed/NCBI
14	Balkwill FR: Cancer and the chemokine network. Nat Rev Cancer. 4:540–550. 2004. View Article : Google Scholar : PubMed/NCBI
15	Azenshtein E, Luboshits G, Shina S, Neumark E, Shahbazian D, Weil M, Wigler N, Keydar I and Ben-Baruch A: The CC chemokine RANTES in breast carcinoma progression: Regulation of expression and potential mechanisms of promalignant activity. Cancer Res. 62:1093–1102. 2002.PubMed/NCBI
16	D’Esposito V, Liguoro D, Ambrosio MR, Collina F, Cantile M, Spinelli R, Raciti GA, Miele C, Valentino R, Campiglia P, et al: Adipose microenvironment promotes triple negative breast cancer cell invasiveness and dissemination by producing CCL5. Oncotarget. 7:24495–24509. 2016.
17	Lee Y, Jung WH and Koo JS: Adipocytes can induce epithelial-mesenchymal transition in breast cancer cells. Breast Cancer Res Treat. 153:323–335. 2015. View Article : Google Scholar : PubMed/NCBI
18	Yang L, Lin C and Liu ZR: P68 RNA helicase mediates PDGF-induced epithelial mesenchymal transition by displacing Axin from beta-catenin. Cell. 127:139–155. 2006. View Article : Google Scholar : PubMed/NCBI
19	Shang X and Yuan Z: Determination of six components in Rhubarb by cyclodextrin-modified micellar electrokinetic chromatography using a mixed micellar system of sodium cholate and sodium taurocholate. Analytica Chimica Acta. 456:183–188. 2002. View Article : Google Scholar
20	Xia XM, Li BK, Xing SM and Ruan HL: Emodin promoted pancreatic claudin-5 and occludin expression in experimental acute pancreatitis rats. World J Gastroenterol. 18:2132–2139. 2012. View Article : Google Scholar : PubMed/NCBI
21	Zhou M, Xu H, Pan L, Wen J, Guo Y and Chen K: Emodin promotes atherosclerotic plaque stability in fat-fed apolipoprotein E-deficient mice. Tohoku J Exp Med. 215:61–69. 2008. View Article : Google Scholar
22	Guo J, Li W, Shi H, Xie X, Li LR, Tang H, Wu M, Kong Y, Yang L, Gao J, et al: Synergistic effects of curcumin with emodin against the proliferation and invasion of breast cancer cells through upregulation of miR-34a. Mol Cell Biochem. 382:103–111. 2013. View Article : Google Scholar : PubMed/NCBI
23	Huang Z, Chen G and Shi P: Effects of emodin on the gene expression profiling of human breast carcinoma cells. Cancer Detect Prev. 32:286–291. 2009. View Article : Google Scholar : PubMed/NCBI
24	Zu C, Zhang M, Xue H, Cai X, Zhao L, He A, Qin G, Yang C and Zheng X: Emodin induces apoptosis of human breast cancer cells by modulating the expression of apoptosis-related genes. Oncol Lett. 10:2919–2924. 2015. View Article : Google Scholar
25	Lin SZ, Wei WT, Chen H, Chen KJ, Tong HF, Wang ZH, Ni ZL, Liu HB, Guo HC and Liu DL: Antitumor activity of emodin against pancreatic cancer depends on its dual role: Promotion of apoptosis and suppression of angiogenesis. PLoS One. 7:e421462012. View Article : Google Scholar : PubMed/NCBI
26	Liu A, Sha L, Shen Y, Huang L, Tang X and Lin S: Experimental study on anti-metastasis effect of emodin on human pancreatic cancer. Zhongguo Zhong Yao Za Zhi. 36:3167–71. 2011.In Chinese.
27	He L, Bi JJ, Guo Q, Yu Y and Ye XF: Effects of emodin extracted from Chinese herbs on proliferation of non-small cell lung cancer and underlying mechanisms. Asian Pac J Cancer Prev. 13:1505–1510. 2012. View Article : Google Scholar : PubMed/NCBI
28	Yu JQ, Bao W and Lei JC: Emodin regulates apoptotic pathway in human liver cancer cells. Phytother Res. 27:251–257. 2013. View Article : Google Scholar
29	Cha TL, Qiu L, Chen CT, Wen Y and Hung MC: Emodin down-regulates androgen receptor and inhibits prostate cancer cell growth. Cancer Res. 65:2287–2295. 2005. View Article : Google Scholar : PubMed/NCBI
30	Xue H, Chen Y, Cai X, Zhao L, He A, Guo K and Zheng X: The combined effect of survivin-targeted shRNA and emodin on the proliferation and invasion of ovarian cancer cells. Anticancer Drugs. 24:937–944. 2013. View Article : Google Scholar : PubMed/NCBI
31	Ma YS, Weng SW, Lin MW, Lu CC, Chiang JH, Yang JS, Lai KC, Lin JP, Tang NY, Lin JG and Chung JG: Antitumor effects of emodin on LS1034 human colon cancer cells in vitro and in vivo: Roles of apoptotic cell death and LS1034 tumor xenografts model. Food Chem Toxicol. 50:1271–1278. 2012. View Article : Google Scholar : PubMed/NCBI
32	Wang W, Sun Y, Li X, Li H, Chen Y, Tian Y, Yi J and Wang J: Emodin potentiates the anticancer effect of cisplatin on gallbladder cancer cells through the generation of reactive oxygen species and the inhibition of survivin expression. Oncol Rep. 26:1143–1148. 2011.PubMed/NCBI
33	Sun Y, Wang X, Zhou Q, Lu Y, Zhang H, Chen Q, Zhao M and Su S: Inhibitory effect of emodin on migration, invasion and metastasis of human breast cancer MDA-MB-231 cells in vitro and in vivo. Oncol Rep. 33:338–346. 2015. View Article : Google Scholar
34	Yan Y, Su X, Liang Y, Zhang J, Shi C, Lu Y, Gu L and Fu L: Emodin azide methyl anthraquinone derivative triggers mitochondrial-dependent cell apoptosis involving in caspase-8-mediated Bid cleavage. Mol Cancer Ther. 7:1688–1697. 2008. View Article : Google Scholar : PubMed/NCBI
35	Isakson P, Hammarstedt A, Gustafson B and Smith U: Impaired preadipocyte differentiation in human abdominal obesity: Role of Wnt, tumor necrosis factor-alpha, and inflammation. Diabetes. 58:1550–1557. 2009. View Article : Google Scholar : PubMed/NCBI
36	Poulos SP, Hausman DB and Hausman GJ: The development and endocrine functions of adipose tissue. Mol Cell Endocrinol. 323:20–34. 2010. View Article : Google Scholar
37	Duband JL, Monier F, Delannet M and Newgreen D: Epithelium-mesenchyme transition during neural crest development. Acta Anat. 154:63–78. 1995. View Article : Google Scholar : PubMed/NCBI
38	Kalluri R and Neilson EG: Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest. 112:1776–1784. 2003. View Article : Google Scholar : PubMed/NCBI