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The Anti-Metastatic Effects of the Phytoestrogen Arctigenin on Human Breast Cancer Cell Lines Regardless of the Status of ER Expression

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The Anti-Metastatic Effects of the Phytoestrogen Arctigenin on Human Breast Cancer Cell Lines Regardless of the Status of ER Expression INTERNATIONAL JOURNAL OF ONCOLOGY 50: 727-735, 2017 The anti-metastatic effects of the phytoestrogen arctigenin on human breast cancer cell lines regardless of the status of ER expression THRESSI MAxwEll, So-YouNg CHuN, KYu-SHIK lEE, SoYouNg KIM and KYuNg-Soo NAM Department of Pharmacology and Intractable Disease Research Center, School of Medicine, Dongguk university, gyeongju-si 780-350, Republic of Korea Received August 8, 2016; Accepted December 12, 2016 DoI: 10.3892/ijo.2016.3825 Abstract. Arctigenin is a plant lignan extracted from Arctium were analyzed using western blotting. The activation of Akt, lappa that has been shown to have estrogenic properties. In NF-κB and MAPK (ERK 1/2 and JNK 1/2) was found to be spite of the health benefits of phytoestrogens reducing the risk inhibited. Taken together, these data suggest that arctigenin of osteoporosis, heart disease, and menopausal symptoms, its confers anti-metastatic effects by inhibiting MMP-9 and uPA benefits against the risk of breast cancer have not been fully via the Akt, NF-κB and MAPK signaling pathways on breast elucidated. Thus, we investigated the effects of arctigenin cancer, regardless of ER expression. Therefore, we propose on metastasis of breast cancer using both estrogen receptor that the intake of arctigenin could be an effective supplement (ER)-positive MCF-7 and ER-negative MDA-MB-231 human for breast cancer patients. breast cancer cell lines to see if the effects are dependent on the status of ER expression. In ER-positive MCF-7 cells, Introduction arctigenin efficiently inhibited 12-O-tetradecanoylphorbol- 13-acetate (TPA)-induced cell migration and invasion. The Arctigenin is a phenylpropanoid dibenzyl butyrolactone lignan activity of crucial metastatic protease matrix metallopro- (Fig. 1) found in members of the Asteraceae family eg: Arctium tease (MMP)-9 in gelatin zymography was also efficiently lappa (1). Arctium lappa, commonly known as burdock, decreased by arctigenin, as well as its mRNA expression. and its extracts have long been consumed in Europe, North Notably, arctigenin exhibited similar anti-metastatic effects America and Asia. It is also traditionally used in folk medicine even in ER-negative MDA-MB-231 cells, suggesting that the for treating sore throat and various infections. Several studies anti-metastatic effects of arctigenin were not exerted via the have shown that arctigenin possesses therapeutic effects for ER. The upstream signaling pathways involved in the regula- anti-viral (2-4), anti-inflammatory (5,6), immune modula- tion of MMP-9 and urokinase plasminogen activator (uPA) tory (7-10) and antitumor activities. Particularly, the antitumor activity of arctigenin has drawn much scientific interest and it has been tested in various human cancer cell lines, showing promising results in cancer cells of the stomach (11,12), liver (12), pancreas (13,14), intestine (15-17), lung (12,18,19), Correspondence to: Dr Kyung-Soo Nam or Dr Soyoung Kim, Department of Pharmacology and Intractable Disease Research bladder (20) and ovaries (21). Regarding the effects of arcti- Center, School of Medicine, Dongguk university, 123 Dongdae-ro, genin in breast cancers, Hsieh et al (22) showed that arctigenin gyeongju-si 780-350, Republic of Korea markedly inhibited the growth of ER-negative MDA-MB-231 E-mail: [email protected] cells by triggering the mitochondrial caspase-independent E-mail: [email protected] apoptotic pathway. However, as lignans have been identified as phytoestrogens, arctigenin has also been reported to have Abbreviations: ER, estrogen receptor; RT-PCR, reverse estrogenic properties (23), making it an interesting candidate transcriptase-polymerase chain reaction; TPA, 12-O-tetradecanoyl- as breast and other hormone responsive cancer treatments. phorbol-13-acetate; MMP, matrix metalloprotease; TIMP, tissue When breast cancers express estrogen receptors, estrogen inhibitor of metalloprotease; uPA, urokinase plasminogen activator; is considered to promote tumor growth. Since phytoestro- uPAR, urokinase plasminogen activator receptor; Akt, protein gens are plant-derived chemicals that are structurally and/or kinase B; NF-κB, nuclear factor kappa B; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; JNK, functionally similar to estrogen, the role of phytoestrogens c-Jun N-terminal kinase; AP-1, activator protein-1; PKC, protein in breast cancer therapy is a highly debated topic (24,25). kinase C; gAPDH, glyceraldehyde-3-phosphate dehydrogenase Although their affinities to estrogen receptors are lower than that of estrogen, it is still of concern that a high intake of Key words: arctigenin, phytoestrogen, metastasis, estrogen receptor, phytoestrogen may promote estrogen-dependent transcription, MCF-7 and MDA-MB-231 human breast cancer cells leading to increased risk in breast cancer patients, especially those treated with hormone therapy to reduce estrogen effects 728 MAxwEll et al: arctigenin oN metastasis in MCF-7 and MDA-MB-231 Human breast cancer cellS St. Louis, Mo, uSA) was used to induce cell migration in MCF-7 cells, while the treatment of TPA was omitted in MDA-MB-231 cells due to their inherent invasive properties. Two independent experiments were done in duplicate wells and optical microscopic images were captured from two different areas of each well at 0 and 24 h. The area between the wound edges was measured at each time-point using ImageJ software as described before (31). wound closure was quantified as previously described (32). Figure 1. Chemical structure of arctigenin (3R,4R)-4-[(3,4-dimethoxyphenyl) methyl]-3-[(4-hydroxy-3-methoxyphenyl)methyl]-2-tetrahydrofuranone. Matrigel invasion assay. The effect of arctigenin on the inva- siveness of human breast cancer cells were determined using Matrigel and Transwell chambers (Corning life Sciences) with within the breast tissue. However, there is growing evidence 8.0-µm pore polycarbonate filter inserts in 24-well plates. The that phytoestrogens have a protective effect on the initiation lower face of the polycarbonate filter (Transwell insert) was of breast cancers by inhibiting the enzymes involved in the coated with Matrigel for 1 h at 37˚C. After coating, 3x104 cells synthesis of estrogen, resulting in the reduced production of were seeded into the Transwell chamber and 750 µl culture estrogen (26-28). Moreover, the low rates of breast cancer in media was added to the lower chamber. After 24 h, cells were Asia imply the health benefit of soy phytoestrogen, which is treated with conditioned media containing 2% FBS and 0, abundant in traditional Asian diet, in reducing the risk of breast 10, 50 and 200 µM arctigenin (Santa Cruz Biotechnology). cancer. Thus, it is still questionable whether phytoestrogens TPA (100 nM) was used to induce only MCF-7 cells and not have beneficial effects against the risk of breast cancers, and the innately invasive MDA-MB-231 cells. The media in the determine the necessity for breast cancer patients to increase bottom chamber was also changed to media containing 10% the intake of arctigenin or arctigenin-enriched foods. FBS and incubated at 37˚C in 5% Co2 atmosphere for 24 h. Despite the successful treatment of the primary tumor, Cells that migrated across the membrane were then fixed metastasis is a major cause of lethality in cancer patients. It and stained using hematoxylin and eosin (H&E) staining was reported that 30-75% of patients undergoing surgery and and photographed under an inverted microscope using x200 adjuvant treatment developed recurrent metastatic disease and magnification. the median survival of patients with metastatic breast cancer is approximately 2 years (29,30). Zhang et al (15) reported Protein extraction and western blot analysis. The cells were that arctigenin inhibited HCT116 colon cancer cell migra- treated with conditioned media containing 0, 10, 25, 50, 100 tion and invasion through the regulation of the H1F4A and and 200 µM arctigenin for 24 h. For induction of invasive Wnt/β catenin pathways. However, to the best of our knowl- characteristics, 100 nM TPA was added for 1 h and then cells edge, the anti-metastatic effect of arctigenin has not been were harvested for protein extraction. The cells were lysed with clearly evaluated on breast cancer cells to date. In this study, RIPA buffer (50 mM Tris-HCl pH 7.5 with 150 mM NaCl, 1% we assessed the anti-metastatic effects of arctigenin on breast Triton x-100, 1% sodium deoxycholate, 0.1% sodium dodecyl cancer cells. In order to check if the effects of the phytoes- sulphate-SDS and 2 mM EDTA) containing phosphatase and trogen arctigenin depended on the status of ER expression we protease inhibitor cocktail (genDEPoT, Barker, Tx, uSA). employed both estrogen receptor (ER)-positive MCF-7 and lysates were cleared of debris at 13,000 rpm for 20 min at 4˚C ER-negative MDA-MB-231 human breast cancer cell lines. and protein concentrations were determined using bicincho- ninic acid reagent (BCA; Sigma-Aldrich). The proteins were Materials and methods separated by SDS-PAgE and transferred onto the polyvinyli- dene fluoride (PVDF) membranes at 100 V for 40 min. The Cell culture. MCF-7 and MDA-MB-231 human breast cancer membranes were blocked in 5% skim milk in Tris-buffered cell lines were purchased from the Korean Cell line Bank saline Tween-20 buffer (10 mM Tris-HCl, 150 mM NaCl and (Seoul, Korea). MCF-7 cells were cultured in Dulbecco's modi- 0.1% Tween-20) for 1 h at room temperature. All primary anti- fied Eagle's medium (DMEM) supplemented with 10% fetal bodies were from Cell Signaling Technology (Beverly, MA, bovine serum (fbs) and 10 µg/ml insulin (all from welgene uSA), were diluted 3,000 times and incubated with blots over- Inc., Daegu, Korea). MDA-MB-231 cells were cultured in night at 4˚C: phospho (#4060) and total (#4691) Akt, phospho DMEM supplemented with 10% FBS only. All media also (#3033) and total (#8242) NF-κB, phospho (#4370) and total contained 1% antibiotic-antimycotic solution (welgene).
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