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Genistein suppressed epithelial-mesenchymal transition and migration efficacies of BG-1 ovarian cancer cells activated by estrogenic chemicals via estrogen receptor pathway and downregulation of TGF-[beta] signaling pathway.

ABSTRACT

Background: Epithelial-mesenchymal transition (EMT), which is activated by 17/[beta]-estradiol (E2) in estrogenresponsive cancers, is an important process in tumor migration or progression. As typical endocrine disrupting chemicals (EDCs), bisphenol A (BPA) and nonylphenol (NP) have a potential to promote EMT and migration of estrogen-responsive cancers. On the contrary, genistein (GEN) as a phytoestrogen is known to have chemopreventive effects in diverse cancers.

Methods: In the present study, the effects of BPA and GEN on EMT and the migration of BG-1 ovarian cancer cells and the underlying mechanism were investigated. ICI 182,780, an estrogen receptor (ER) antagonist, was co-treated with E2 or BPA or NP to BG-1 cells to identify the relevance of ER signaling in EMT and migration.

Results: As results, E2 and BPA upregulated the protein expression of vimentin, cathepsin D, and MMP-2, but downregulated the protein expression of E-cadherin via ER signaling pathway, suggesting that E2 and BPA promote EMT and cell migration related gene expressions. However, the increased protein expressions of vimentin, cathepsin D, and MMP-2 by E2, BPA, or NP were reduced by the co-treatment of GEN. In a scratch assay, the migration capability of BG-1 cells was enhanced by E2, BPA, and NP via ER signaling but reversed by the co-treatment of GEN. in the protein expression of SnoN and Smad3, E2, BPA, and NP upregulated SnoN, a negative regulator of TGF-[beta] signaling, and downregulated pSmad3, a transcription factor in the downstream pathway of TGF-[beta] signaling pathway, suggesting that E2, BPA, and NP simultaneously lead to the downregualtion of TGF-[beta] signaling in the process of induction of EMT and migration of BG-1 cells via ER signaling. On the other hand, the co-treatment of GEN reversed the downregulation of TGF-[beta] signaling by estrogenic chemicals.

Conclusion: Taken together, GEN suppressed EMT and migration capacities of BG-1 ovarian cancer cells enhanced by E2, BPA, and NP via ER signaling and the downregulation of TGF-[beta] signal.

Keywords:

Cancer migration

EMT

Genistein

Ovarian cancer

Introduction

Ovarian cancer is a very dangerous type of cancer causing death of women. In the United States, 21,980 new cases were diagnosed with ovarian cancer, and the death of more than 50% of those cases was estimated in 2014 (Siegel et al. 2014). The reason of ovarian cancer patients having low survival rates is thought to be frequent recurrence and fast metastasis of ovarian cancer (Jin et al. 2010). Moreover, it was reported that ovarian cancer stem cells, which have the capacity to differentiate into the various cell types that compose the tumor mass, have resistibility to typical chemical therapy (Ponnusamy and Batra 2008). Therefore, efficient treatments are needed to restrain aggressiveness and increase a cure of ovarian cancer. As means of cancer remedy, many studies have focused on phytoestrogens, which are estrogenic compounds found in plants and are known to have anticarcinogenic effects (Gercel-Taylor et al. 2004; Jin and MacDonald 2002; Kim and Choi 2013; Solomon et al. 2008).

Interest in phytoestrogens has been originally launched from the epidemiological studies showing that Asian people who consume significantly higher amounts of phytoestrogens have lower incidence rate of breast and prostate cancer than western people who consume relatively less phytoestrogens (Aufderklamm et al. 2014; Kim et al. 2014). Of many phytoestrogens, genistein (GEN), 4',5,7-trihydroxyisoflavone, was firstly extracted from dyer's broom by Perkin. This compound belongs to isoflavone family and is usually found in soybeans, peas, lentils, and other beans (Messina et al. 2006). Because the structure of GEN is similar to that of estrogen, GEN can well bind to two isoforms of estrogen receptor (ER), ER-[alpha] and ER-[beta] (Kim et al. 2014; Pavese et al. 2010). Of the two receptors, the binding affinity of GEN for ER-[beta] is about 20 times higher than that for ER-[alpha], indicating that GEN has been related with its action as chemopreventive activity resulting from an estrogen antagonist. Several studies have reported that GEN significantly inhibited the growth, metastasis and angiogenesis of various types of cancer (Kim et al. 2014; Lakshman et al. 2008; Pavese et al. 2014; Piao et al. 2006; Zhang et al. 2013). In other studies using animal models, it was also reported that GEN has therapeutic effects in many diseases other than cancer and further inhibits cytokine-induced signals by participating in the immune system (Gupta et al. 2011; Verdrengh et al. 2003). On the contrary, GEN was shown to be related with cancer occurrence in breast, prostate, and liver (Dai et al. 2013; Hwang et al. 2009; Wu et al. 1996). The conflicting effects of GEN seem to be related with the exposure concentrations of GEN. A previous research suggests that GEN shows a biphasic effect in ER-positive breast cancer. Low concentration (10-100 nM) of GEN increased growth of MCF-7 breast cancer cells, however, cell proliferation was inhibited in high concentration (20 [micro]M) of GEN (Hsieh et al. 1998).

Epithelial-mesenchymal transition (EMT) is an important process in cancer metastasis. The morphology of cancer cells changes into more invasive form through EMT. As a result, EMT facilitates cancer metastasis by helping cancer cells penetrate into blood and settle in a new nest (Kim et al. 2014). TGF-[beta] superfamily is related with embryo development and several diseases such as cancer and fibrosis by binding to cellular receptor and then inducing EMT process. TGF-[beta] induced EMT and metastasis via Smad2 pathway in breast cancer and IL-6/JAK/STAT3 pathway in lung cancer, respectively (Liu et al. 2014; Lvet al. 2013).

In the previous study, we reported that 17 [beta]-estradiol (E2) increased cancer proliferation, and GEN effectively suppressed E2 induced proliferation in ER-positive BG-1 ovarian cancer models (Hwang et al. 2013). Furthermore, in this study, we investigated whether E2 or bisphenol A (BPA) and nonylphenol (NP), typical endocrine disrupting chemicals (EDCs), can induce EMT response, and whether GEN can inhibit EMT and metastasis induced by E2 or BPA in BG-1 ovarian cancer cells. For this purpose, we confirmed the alterations in protein expressions related with EMT and migration and the relevance of TGF-[beta] signaling, which is well known as an accelerant of metastasis, to elucidate the underlying mechanism.

Materials and methods

Reagents and chemicals

E2, BPA, and NP were obtained from Sigma-Aldrich Corp. (St. Louis, MO, USA), and GEN was purchased from LC Laboratories (Woburn, MA, USA). All chemicals were dissolved in dimethyl sulfoxide (DMSO; Junsei Chemical Co., Tokyo, Japan), and the mixtures were stored at room temperature.

Cell culture

BG-1 human ovarian cancer cells were obtained from Dr. K.S. Korach (National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC, USA). The cells were cultured at 37[degrees]C in humidified atmosphere of 5% C[O.sub.2]-95% air. Cell culture medium contains Dulbecco's modified Eagle's medium (DMEM; Hydone Laboratories Inc., Logan, USA) supplemented with 10% inactivated fetal bovine serum (FBS; Hyclone Laboratories Inc.), 1% antifungal HEPES (Invitrogen Life Technologies, Carlsbad, CA, USA), and 1% penicillin G and streptomycin (Life Technologies, Rockville, MD, USA). Because DMEM and FBS may have estrogenic components, we cultured BG-1 cells in phenol red-free DMEM containing 5% charcoal-dextran treated FBS (CD-FBS) to confirm estrogenicity of BPA and NP as previously described (Hwang et al. 2013; Kang et al. 2013). The cells were detached by 0.05% trypsin/0.02% EDTA in [Mg.sup.2+]/[Ca.sup.2+] (Gibco, Carlsbad, CA, USA).

Protein extraction

BG-1 cells were treated with DMSO (0.1%), E2 ([10.sup.-7]), BPA ([10.sup.-6] M), or NP ([10.sup.-6] M) individually or DMSO (0.1%), E2 ([10.sup.-7] M), BPA ([10.sup.-6] M), or NP ([10.sup.-6] M) in combination with ICI 182,780 ([10.sup.-6] M) or GEN ([10.sup.-4] M), for 1 or 48 h. Proteins were extracted by using 1 x RIPA lysis buffer (50 mM Tris-HCl, pH 8.0; 150 mM NaCl, 1% NP-40, 0.5% deoxycholic acid, and 0.1% SDS). Concentration of the proteins was quantified by using bicinchoninc acid (BCA; Sigma-Aldrich Co.) method.

Western blot analysis

The proteins were separated on 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred into polyvinylidene fluoride (PVDF) membrane (Bio-Rad Laboratories, Inc., Hercules, CA, USA). Membranes were blocked by 5% skimmilk (Bio-Rad Laboratories, Inc.) for 2 h in room temperature and incubated with mouse monoclonal anti-GAPDH antibody (1:5000, Abeam pic., Cambridge, UK), mouse monoclonal anti-vimentin antibody (1:1000, Abeam pic.), rabbit polyclonal anti-E-cadherin antibody (1:1000, Abeam pic.), rabbit monoclonal anti-MMP-2 antibody (1:1000, Abeam pic.), rabbit polyclonal anti-cathepsin D antibody (1:10000, Abeam pic.), rabbit monoclonal anti-pSmad 3 antibody (1:200, Santa Cruz Biotechnology, Santa Cruz, CA, USA) and mouse monoclonal anti-SnoN antibody (1:200, Santa Cruz Biotechnology) for 2 h at room temperature. Additionally membranes were incubated with anti-mouse IgG-horse radish peroxidase (HRP) conjugated secondary antibody (1:2000, Santa Cruz Biotechnology) and anti-rabbit IgG-HRP conjugated secondary antibody (1:2000, Santa Cruz Biotechnology). Proteins attached on membranes were visualized by using ECL chemical luminescent system (GenDEPOT). Band density was estimated by using Gel Doc 2000. Protein expression levels were normalized by GAPDH protein.

Scratch assay

BG-1 cells were cultured at 8 x [10.sup.5] cells/well of 6-well plates at 37[degrees]C in a humidified atmosphere of 5% C[O.sub.2]-95% air for 48 h. The cells were scratched and washed with PBS to remove cell debris. The cells were then treated with 5% CD-FBS phenol free media supplemented with DMSO (0.1%), E2 ([10.sup.-7] M), BPA ([10.sup.-6] M), or NP ([10.sup.-6] M) individually or DMSO (0.1%), E2 ([10.sup.-7] M), BPA ([10.sup.-6] M), or NP ([10.sup.-6] M) in combination with ICI 182,780 ([10.sup.-6] M) or GEN ([10.sup.-4] M), for 48 h. The pictures were taken with a microscope under 4x magnification at 0 and 48 h after scratch. The percentage of unrecovered wound area was calculated by dividing the uncovered area at 48 h with the initial wound area at time zero.

Statistics analysis

All experiments were repeated at least 3 times and data were presented as mean [+ or -] S.D. Statistical analysis was conducted by using one-way ANOVA test, followed by Dunnett's multiple comparison test. Differences with p-value <0.05 were considered statistically significant.

Results

GEN inhibits EMT induced by E2 and estrogenic EDCs

To investigate the effects of E2, BPA, and NP on EMT response of BG-1 ovarian cancer cells, the alterations in protein expression of typical EMT markers, vimentin and E-cadherin, were measured after 48 h of the treatment of each reagent to BG-1 cells. Protein level of vimentin was increased more than 1.3-fold by E2, BPA, and NP compared to a control (DMSO) (p < 0.05, Fig. 1A and B), but protein expression of E-cadherin was decreased by E2, BPA, or NP about 20% than that by a control (p < 0.05, Fig. 1A and C). This result shows that E2 as well as BPA and NP have the potential to induce EMT process in BG-1 ovarian cancer cells. Next, ICI 182,780, an ER antagonist, was co-treated with E2, BPA, or NP to examine whether EMT response by each reagent is mediated via ER signaling. Co-treatment with ICI 182,780 restored the increased or decreased protein expression of vimentin and E-cadherin induced by E2, BPA, and NP into control level (Fig. 1), indicating that EMT response induced by E2, BPA, and NP was mediated by ER signaling, and BPA and NP are apparent estrogenic EDCs. Finally, GEN was co-treated with E2, BPA, or NP to examine the inhibition effect of GEN on EMT. GEN reduced the increased protein expression of vimentin induced by E2 and BPA (Fig. 1A and B), but GEN increased the decreased protein expression of E-cadherin induced by E2, BPA, and NP as seen in Fig. 1A and C, indicating that GEN effectively suppressed the EMT response induced by E2 and two estrogenic EDCs, BPA and NP.

GEN reduced the increased expression of migration markers, MMP2 and cathepsin D, induced by E2, BPA, and NP

To investigate whether E2, BPA, NP, and GEN could affect the migration of BG-1 ovarian cancer cells, the alterations in protein expression of MMP2 and cathepsin D which are used as cell migration and metastatic markers (Lee and Choi 2013) for being actively expressed during cancer metastasis process were measured after 48 h of the treatment of each reagent to BG-1 cells. The single treatment of E2, BPA, or NP significantly induced protein expression of MMP2 (about 1.4-fold, Fig. 2A and B) and cathepsin D (more than twice, Fig. 2A and C) compared to a control (p < 0.05). However, the co-treatment of ICI 182,780 with E2, BPA, or NP significantly reduced the protein expression levels of MMP2 and cathepsin D whose expressions were increased by each single treatment into the control level or less as shown in Fig. 2, which also means that the cell migration process promoted by E2, BPA, and NP was mediated by ER signaling. Moreover, the additional treatment of GEN into each medium containing E2, BPA, or NP also restored the protein expression of MMP2 (Fig. 2A and B) and cathepsin D (Fig. 2A and C) increased by E2, BPA, and NP to the control level (p < 0.05), which implies that GEN effectively inhibited the migration capacity of BG-1 cells promoted by E2 and two estrogenic EDCs, BPA and NP.

Migration ability promoted by E2 and two EDCs was reduced by treatment of GEN

To confirm whether the changes in protein levels of EMT and cell migration markers match the alterations in actual cell migration capacity, a scratch assay, which measures the changes in the scratched area in a cell culture plate after treatment of a reagent, was performed. After 48 h of E2, BPA, or NP treatment, the uncovered scratched area was decreased than that of control, which means that E2, BPA, and NP could increase the migration capacity of BG-1 ovarian cancer cells as shown in Fig. 3A and D. However, co-treatment of ICI 182,780 with E2, BPA, or NP restored the changes in cell migration into the level of control, indicating that the cell migration process promoted by E2, BPA, and NP was mediated via ER signaling (Fig. 3B and D). In addition, uncovered area in co-treatment group of E2, BPA, or NP with GEN did not decrease as much as that in single treatment of each reagent was reduced as seen in Fig. 3C and D. One interesting thing is that single treatment of GEN showed a declining tendency of unrecovered area compared to that of control. In spite of this tendency, it can be said that GEN virtually inhibits the migration capacity of BG-1 ovarian cancer cells promoted by E2, BPA, and NP.

E2 and TGF-[beta] signals have a reversed relation in BG-1 cell migration

To investigate the relevance of TGF-[beta] signaling and the relation between ER and TGF-[beta] signals in BG-1 ovarian cancer cell migration, the protein expression of two factors of TGF-[beta] signaling, pSmad and SnoN, was assayed after the treatment of E2, BPA, NP, ICI, 182,780, or GEN. In the single treatment of E2, BPA, or NP, the protein expression of pSmad 3, a representative downstream molecule of TGF-[beta] signaling, was decreased by about half that of a control (Fig. 4A and B), however, the protein expression of SnoN, an inhibitor of TGF-[beta] signaling, was increased compared to that of control (Fig. 4A and C) (p < 0.05). When co-treated with ICI 182,780 with E2, BPA, or NP, the protein expression level of pSmad 3 was restored into the control level, and the expression of SnoN protein was more decreased than that of control as demonstrated in Fig. 4. In addition, co-treatment of GEN increased the protein expression of pSmad 3 compared to that of single treatment of E2, BPA, or NP (Fig. 4A and B) but reduced SnoN expression compared to that of single treatment of each reagent (Fig. 4A and C) (p < 0.05). These results showed that E2 and two EDCs, BPA and NP, inhibited TGF-[beta] signaling, but GEN reactivated TGF-[beta] signaling suppressed by three reagents.

Discussion

EDCs are known to adversely affect human health by disrupting the action of endogenous steroid hormones (Masuo and Ishido 2011; Phillips and Tanphaichitr 2008). Recently, EDCs have emerged as a risk factor for hormone-responsive cancers (Flwang et al. 2011; Lee et ai. 2011; Soto and Sonnenschein 2010). They may be involved in various stages of cancer such as carcinogenesis and metastasis (Ferreira et al. 2015; Zhu et al. 2010). In the present study, it was investigated whether BPA and NP, typical EDCs, can affect EMT process and migration of estrogen-responsive BG-1 ovarian cancer cells and further whether GEN, a novel phytoestrogen, can suppress the risk of cancer metastasis imposed by chemical EDCs such as BPA and NP. Firstly, we confirmed that BPA and NP have the potential to promote ovarian cancer metastasis by upregulating vimentin while downregulating E-cadherin and by inducing BG-1 cell migration. From these actions of BPA and NP that coincided with that of E2 and were inhibited by ICI 182,780, which is an ER antagonist suppressing estrogenic effects by blocking ER signaling, they were clearly elucidated to be xenoestrogenic EDCs.

Next, we further identified that GEN could repress metastatic potential of ovarian cancer induced by estrogenic compounds. GEN inhibited EMT response enhanced by E2, BPA, and NP and induced the decrease of metastasis marker expression and migration rate promoted by E2, BPA, and NP. These effects of GEN were similar to that of ICI 182,780, suggesting that GEN functions as an ER antagonist on metastatic activity of BG-1 ovarian cancer cells, which is activated by ER signaling. Meanwhile, another result by GEN was observed in a scratch assay, in which a single treatment of GEN increased BG1 cell migration compared to control. This double sidedness of GEN can be known from several studies. Many studies have reported that GEN suppressed cell growth in prostate, breast cancer, and so on (Kousidou et al. 2005; Lakshman et al. 2008; Myoung et al. 2003). In metastasis research of prostate cancer using athymic mice models, in which PCa cells were orthotopically implanted, and GEN was injected into the mice, GEN decreased metastasis rate of prostate cancer despite blood concentration of GEN in the mice was similar to that of human. As a mechanism explaining that GEN inhibits metastasis of prostate cancer, it was elucidated that functional activities of pro-motility proteins like FAK, p38 MAPK, and HSP27 were reduced by GEN (Lakshman et al. 2008). On the other hand, other study reported that GEN promoted cancer metastasis. In in vivo advanced prostate cancer model, increase of lymph node and secondary metastasis were higher in GEN treated group than in control group. In addition, the cell proliferation was higher, and the apoptosis rate of cancer was lower in GEN treated group than in control group (Nakamura et al. 2011). In addition, it was reported that GEN increased metastatic progression of prostate cancer unlike ICI 182,789 (Nakamura et al. 2013). Although a biphasic effect based on the concentration range of GEN may explain its double sidedness, other factors including type and stage of cancer have to be considered to elucidate the definite effect of GEN on cancer.

In our latest study, it was identified that BPA and NP stimulated the migration of BG-1 cells via an ER dependent pathway (Kim et al. 2015). In the present study, the effect of E2, BPA, NP, and GEN on EMT and migration process of BG-1 ovarian cancer cells was described in accordance with the relation between ER and TGF-[beta] signals. TGF-[beta] signaling is an important pathway to induce EMT response in not only differentiation process of embryo development but also cancer metastasis (Kim et al. 2014; Xu et al. 2009). Contrary to expectation that TGF-[beta] signaling will co-activate EMT and migration process in conjunction with ER signaling, TGF-[beta] signaling appeared to be rather hindered by ER signaling, showing that it was activated by an ER antagonist or GEN. Other study also reported the inhibition of TGF-[beta] signaling by E2, in which mitogen-activated protein kinases (MAPKs) activated by E2 via G protein-coupled receptor 30 (GPR30) inhibited the activation of Smad proteins, downstream molecules of TGF-[beta] signaling (Kleuser et al. 2008). Another study presented that ER degraded Smad proteins by producing ubiquitin Smurf-ERa-Smad complex via nongenomic ER pathway after E2 binging to ER (Ito et al. 2010). Park et al. (2011) also reported that TGF-[beta] is the inhibitor of cell cycle progression in E2 or EDC induced BG-1 ovarian cancer cell proliferation. These opposed results support the dual roles of TGF-[beta] in cancer. Generally, it has been known that TGF-[beta] plays a tumorigenic role or as a tumor suppressor depending on the cellular context and the stage of tumor (Massague 2008; Tirado-Rodriguez et al. 2014). In the condition of the present study, TGF-[beta] signaling may be related with the inhibition of cancer progression. From the results that TGF-[beta] signaling was inhibited by E2 and xenoestrogens, and co-treatment of ICI 182,780 restored the activation of TGF-[beta] signaling, it seems that there is a kind of correlation between ER and TGF-[beta] signals in the way of the inhibition of TGF-[beta] signaling by ER signaling. For GEN, it also restored TGF-[beta] signaling suppressed by ER signaling by inhibiting ER signaling like ICI 182,780.

In conclusion, E2 and the xenoestrogenic EDCs, BPA and NP, induced BG-1 ovarian cancer metastasis by promoting EMT and cell migration via activated ER signaling and also the inhibition of TGF-[beta] signaling by ER signaling as shown in Fig. 5. On the other hand, GEN appeared to suppress the metastatic potential of BG-1 ovarian cancer cells by inhibiting ER signaling and restoring TGF-[beta] signaling pathway as shown in Fig. 5. From this study, the risk of xenoestrogens in cancer progression might be emphasized, and the usefulness of phytoestrogens derived from natural food sources might be raised as a tool for the disease treatment and a healthy diet. In the future study, more researches would be needed to reveal the exact mode of actions of phytoestrogens on the diverse types and stages of cancer for elucidating the controversial issues about phytoestrogens.

ARTICLE INFO

Article history:

Received 17 April 2015

Revised 20 July 2015

Accepted 3 August 2015

Conflict of interest

The authors declare that there is no financial conflict of interests to publish these results.

Acknowledgments

This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (MEST) of the Republic of Korea (2014R1A1A2055295).

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Ye-Seul Kim, Kyung-Chul Choi *, Kyung-A Hwang **

Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea

Abbreviations: EMT, epithelial-mesenchymal transition; E2, 17 [beta]-estradiol; EDCs, endocrine disrupting chemicals; BPA, bisphenol A; NP, nonylphenol; GEN, genistein; ER, estrogen receptor; TGF, transforming growth factor; MMP, matrix-metallo proteinase.

* Corresponding author. Tel.: +82 43 261 3664; fax: +82 43 267 3150.

** Corresponding author. Tel.: +82 43 249 1745; fax: +82 43 267 3150.

E-mail addresses: kchoi@cbu.ac.kr (K.-C. Choi), hka9400@naver.com {K.-A. Hwang).

http://dx.doi.org/10.1016/j.phymed.2015.08.003
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Title Annotation:transforming growth factor
Author:Kim, Ye-Seul; Choi, Kyung-Chul; Hwang, Kyung-A
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Date:Oct 15, 2015
Words:5419
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