Skip to main content
Top
Published in: Journal of Experimental & Clinical Cancer Research 1/2017

Open Access 01-12-2017 | Research

Wogonoside inhibits invasion and migration through suppressing TRAF2/4 expression in breast cancer

Authors: Yuyuan Yao, Kai Zhao, Zhou Yu, Haochuan Ren, Li Zhao, Zhiyu Li, Qinglong Guo, Na Lu

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2017

Login to get access

Abstract

Background

Twist1 is involved in tumor initiation and progression, which especially contributes to tumor invasion and metastasis. Wogonoside is the main in-vivo metabolite of wogonin, and it is also a natural product with potential treatment effects against cancer.

Methods

In this study, we investigated the in-vitro anti-invasion and in-vivo anti-metastasis effects of wogonoside on breast cancer cells and uncovered its underlying mechanism.

Results

The results showed that wogonoside could suppress the growth and metastasis of breast tumor in the orthotopic model of MDA-MB-231 cells. We found that wogonoside could reduce the overexpression of TNF-α, TRAF2 and TRAF4 in later stage of tumor, and improved tumor microenvironment. Therefore, TNF-α was utilized to induce metastases of breast cancer cell in vitro. Wogonoside could inhibit invasion and migration in TNF-α-induced MDA-MB-231, MDA-MB-435, and BT-474 cells. Mechanically, wogonoside inactivated NF-κB signaling through decreasing the protein expression of TRAF2/4, which further inhibited Twist1 expression. Consequently, wogonoside could down-regulate MMP-9, MMP-2, vimentin and CD44v6 expression in TNF-α-induced MDA-MB-231 and MDA-MB-435 cells. Then, these findings were proved in TNF-α + TGF-β1-induced MCF7 cells.

Conclusions

Wogonoside might be a potential therapeutic agent for the treatment of tumor metastasis in breast cancer.
Literature
1.
go back to reference Hollestelle A, Nagel JHA, Smid M, Lam S, Elstrodt F, Wasielewski M, Ng SS, French PJ, Peeters JK, Rozendaal MJ, et al. Distinct gene mutation profiles among luminal-type and basal-type breast cancer cell lines. Breast Cancer Res Treat. 2010;121:53–64.CrossRef Hollestelle A, Nagel JHA, Smid M, Lam S, Elstrodt F, Wasielewski M, Ng SS, French PJ, Peeters JK, Rozendaal MJ, et al. Distinct gene mutation profiles among luminal-type and basal-type breast cancer cell lines. Breast Cancer Res Treat. 2010;121:53–64.CrossRef
2.
go back to reference Williams SL, Birdsong GG, Cohen C, Siddiqui MT. Immunohistochemical Detection of Estrogen and Progesterone Receptor and HER2 Expression in Breast Carcinomas: Comparison of Cell Block and Tissue Block Preparations. Int J Clin Exp Pathol. 2009;2:476–80.PubMedPubMedCentral Williams SL, Birdsong GG, Cohen C, Siddiqui MT. Immunohistochemical Detection of Estrogen and Progesterone Receptor and HER2 Expression in Breast Carcinomas: Comparison of Cell Block and Tissue Block Preparations. Int J Clin Exp Pathol. 2009;2:476–80.PubMedPubMedCentral
3.
go back to reference Ebrahimi M, Ebrahimie E, Shamabadi N, Ebrahimi M. Are there any differences between features of proteins expressed in malignant and benign breast cancers? J Res Med Sci. 2010;15:299–309.PubMedPubMedCentral Ebrahimi M, Ebrahimie E, Shamabadi N, Ebrahimi M. Are there any differences between features of proteins expressed in malignant and benign breast cancers? J Res Med Sci. 2010;15:299–309.PubMedPubMedCentral
4.
go back to reference Loganathan J, Jiang JH, Smith A, Jedinak A, Thyagarajan-Sahu A, Sandusky GE, Nakshatri H, Sliva D. The mushroom Ganoderma lucidum suppresses breast-to-lung cancer metastasis through the inhibition of pro-invasive genes. Int J Oncol. 2014;44:2009–15.CrossRef Loganathan J, Jiang JH, Smith A, Jedinak A, Thyagarajan-Sahu A, Sandusky GE, Nakshatri H, Sliva D. The mushroom Ganoderma lucidum suppresses breast-to-lung cancer metastasis through the inhibition of pro-invasive genes. Int J Oncol. 2014;44:2009–15.CrossRef
5.
go back to reference Aggarwal BB, Shishodia S, Ashikawa K, Bharti AC. The role of TNF and its family members in inflammation and cancer: lessons from gene deletion. Curr Drug Targets Inflamm Allergy. 2002;1:327–41.CrossRef Aggarwal BB, Shishodia S, Ashikawa K, Bharti AC. The role of TNF and its family members in inflammation and cancer: lessons from gene deletion. Curr Drug Targets Inflamm Allergy. 2002;1:327–41.CrossRef
6.
go back to reference Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117:927–39.CrossRef Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117:927–39.CrossRef
7.
go back to reference Weiss MB, Abel EV, Mayberry MM, Basile KJ, Berger AC, Aplin AE. TWIST1 Is an ERK1/2 Effector That Promotes Invasion and Regulates MMP-1 Expression in Human Melanoma Cells. Cancer Res. 2012;72:6382–92.CrossRef Weiss MB, Abel EV, Mayberry MM, Basile KJ, Berger AC, Aplin AE. TWIST1 Is an ERK1/2 Effector That Promotes Invasion and Regulates MMP-1 Expression in Human Melanoma Cells. Cancer Res. 2012;72:6382–92.CrossRef
8.
go back to reference Ansieau S, Bastid J, Doreau A, Morel AP, Bouchet BP, Thomas C, Fauvet F, Puisieux I, Doglioni C, Piccinin S, et al. Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell. 2008;14:79–89.CrossRef Ansieau S, Bastid J, Doreau A, Morel AP, Bouchet BP, Thomas C, Fauvet F, Puisieux I, Doglioni C, Piccinin S, et al. Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell. 2008;14:79–89.CrossRef
9.
go back to reference Maestro R, Dei Tos AP, Hamamori Y, Krasnokutsky S, Sartorelli V, Kedes L, Doglioni C, Beach DH. Hannon GJ: twist is a potential oncogene that inhibits apoptosis. Genes Dev. 1999;13:2207–17.CrossRef Maestro R, Dei Tos AP, Hamamori Y, Krasnokutsky S, Sartorelli V, Kedes L, Doglioni C, Beach DH. Hannon GJ: twist is a potential oncogene that inhibits apoptosis. Genes Dev. 1999;13:2207–17.CrossRef
10.
go back to reference Kwok WK, Ling MT, Lee TW, Lau TCM, Zhou C, Zhang XM, Chua CW, Chan KW, Chan FL, Glackin C, et al. Up-regulation of TWIST in prostate cancer and its implication as a therapeutic target. Cancer Res. 2005;65:5153–62.CrossRef Kwok WK, Ling MT, Lee TW, Lau TCM, Zhou C, Zhang XM, Chua CW, Chan KW, Chan FL, Glackin C, et al. Up-regulation of TWIST in prostate cancer and its implication as a therapeutic target. Cancer Res. 2005;65:5153–62.CrossRef
11.
go back to reference Eckert MA, Lwin TM, Chang AT, Kim J, Danis E, Ohno-Machado L, Yang J. Twist1-induced invadopodia formation promotes tumor metastasis. Cancer Cell. 2011;19:372–86. Eckert MA, Lwin TM, Chang AT, Kim J, Danis E, Ohno-Machado L, Yang J. Twist1-induced invadopodia formation promotes tumor metastasis. Cancer Cell. 2011;19:372–86.
12.
go back to reference Lee TK, Poon RTP, Yuen AP, Ling MT, Kwok WK, Wang XH, Wong YC, Guan XY, Man K, Chau KL, Fan ST. Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res. 2006;12:5369–76.CrossRef Lee TK, Poon RTP, Yuen AP, Ling MT, Kwok WK, Wang XH, Wong YC, Guan XY, Man K, Chau KL, Fan ST. Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res. 2006;12:5369–76.CrossRef
13.
go back to reference Yang Z, Zhang XH, Gang H, Li XJ, Li ZM, Wang T, Han J, Luo T, Wen FQ, Wu XT. Up-regulation of gastric cancer cell invasion by Twist is accompanied by N-cadherin and fibronectin expression. Biochem Biophys Res Commun. 2007;358:925–30.CrossRef Yang Z, Zhang XH, Gang H, Li XJ, Li ZM, Wang T, Han J, Luo T, Wen FQ, Wu XT. Up-regulation of gastric cancer cell invasion by Twist is accompanied by N-cadherin and fibronectin expression. Biochem Biophys Res Commun. 2007;358:925–30.CrossRef
14.
go back to reference Vesuna F, Lisok A, Kimble B, Raman V. Twist modulates breast cancer stem cells by transcriptional regulation of CD24 expression. Neoplasia. 2009;11:1318–28.CrossRef Vesuna F, Lisok A, Kimble B, Raman V. Twist modulates breast cancer stem cells by transcriptional regulation of CD24 expression. Neoplasia. 2009;11:1318–28.CrossRef
15.
go back to reference Li CW, Xia W, Huo L, Lim SO, Wu Y, Hsu JL, Chao CH, Yamaguchi H, Yang NK, Ding Q, et al. Epithelial-mesenchymal transition induced by TNF-alpha requires NF-kappaB-mediated transcriptional upregulation of Twist1. Cancer Res. 2012;72:1290–300.CrossRef Li CW, Xia W, Huo L, Lim SO, Wu Y, Hsu JL, Chao CH, Yamaguchi H, Yang NK, Ding Q, et al. Epithelial-mesenchymal transition induced by TNF-alpha requires NF-kappaB-mediated transcriptional upregulation of Twist1. Cancer Res. 2012;72:1290–300.CrossRef
16.
go back to reference Li H, Hui H, Xu J, Yang H, Zhang X, Liu X, Zhou Y, Li Z, Guo Q, Lu N. Wogonoside induces growth inhibition and cell cycle arrest via promoting the expression and binding activity of GATA-1 in chronic myelogenous leukemia cells. Arch Toxicol. 2016;90:1507–22.CrossRef Li H, Hui H, Xu J, Yang H, Zhang X, Liu X, Zhou Y, Li Z, Guo Q, Lu N. Wogonoside induces growth inhibition and cell cycle arrest via promoting the expression and binding activity of GATA-1 in chronic myelogenous leukemia cells. Arch Toxicol. 2016;90:1507–22.CrossRef
17.
go back to reference Huang Y, Zhao K, Hu Y, Zhou Y, Luo X, Li X, Wei L, Li Z, You Q, Guo Q, Lu N. Wogonoside inhibits angiogenesis in breast cancer via suppressing Wnt/beta-catenin pathway. Mol Carcinog. 2016;55:1598–612. Huang Y, Zhao K, Hu Y, Zhou Y, Luo X, Li X, Wei L, Li Z, You Q, Guo Q, Lu N. Wogonoside inhibits angiogenesis in breast cancer via suppressing Wnt/beta-catenin pathway. Mol Carcinog. 2016;55:1598–612.
18.
go back to reference Sun Y, Zhao Y, Yao J, Zhao L, Wu Z, Wang Y, Pan D, Miao H, Guo Q, Lu N. Wogonoside protects against dextran sulfate sodium-induced experimental colitis in mice by inhibiting NF-kappaB and NLRP3 inflammasome activation. Biochem Pharmacol. 2015;94:142–54.CrossRef Sun Y, Zhao Y, Yao J, Zhao L, Wu Z, Wang Y, Pan D, Miao H, Guo Q, Lu N. Wogonoside protects against dextran sulfate sodium-induced experimental colitis in mice by inhibiting NF-kappaB and NLRP3 inflammasome activation. Biochem Pharmacol. 2015;94:142–54.CrossRef
19.
go back to reference Cheng Y, Zhao K, Li G, Yao J, Dai Q, Hui H, Li Z, Guo Q, Lu N. Oroxylin A inhibits hypoxia-induced invasion and migration of MCF-7 cells by suppressing the Notch pathway. Anti-Cancer Drugs. 2014;25:778–89.CrossRef Cheng Y, Zhao K, Li G, Yao J, Dai Q, Hui H, Li Z, Guo Q, Lu N. Oroxylin A inhibits hypoxia-induced invasion and migration of MCF-7 cells by suppressing the Notch pathway. Anti-Cancer Drugs. 2014;25:778–89.CrossRef
20.
go back to reference Lu Z, Lu N, Li C, Li F, Zhao K, Lin B, Guo Q. Oroxylin A inhibits matrix metalloproteinase-2/9 expression and activation by up-regulating tissue inhibitor of metalloproteinase-2 and suppressing the ERK1/2 signaling pathway. Toxicol Lett. 2012;209:211–20.CrossRef Lu Z, Lu N, Li C, Li F, Zhao K, Lin B, Guo Q. Oroxylin A inhibits matrix metalloproteinase-2/9 expression and activation by up-regulating tissue inhibitor of metalloproteinase-2 and suppressing the ERK1/2 signaling pathway. Toxicol Lett. 2012;209:211–20.CrossRef
21.
go back to reference Chakrabarti R, Kang Y. Transplantable mouse tumor models of breast cancer metastasis. Methods Mol Biol. 2015;1267:367–80.CrossRef Chakrabarti R, Kang Y. Transplantable mouse tumor models of breast cancer metastasis. Methods Mol Biol. 2015;1267:367–80.CrossRef
22.
go back to reference Wang H, Zhao L, Zhu LT, Wang Y, Pan D, Yao J, You QD, Guo QL. Wogonin reverses hypoxia resistance of human colon cancer HCT116 cells via downregulation of HIF-1alpha and glycolysis, by inhibiting PI3K/Akt signaling pathway. Mol Carcinog. 2014;53(Suppl 1):E107–18.CrossRef Wang H, Zhao L, Zhu LT, Wang Y, Pan D, Yao J, You QD, Guo QL. Wogonin reverses hypoxia resistance of human colon cancer HCT116 cells via downregulation of HIF-1alpha and glycolysis, by inhibiting PI3K/Akt signaling pathway. Mol Carcinog. 2014;53(Suppl 1):E107–18.CrossRef
23.
go back to reference Jiang J, Thyagarajan-Sahu A, Loganathan J, Eliaz I, Terry C, Sandusky GE, Sliva D. BreastDefend prevents breast-to-lung cancer metastases in an orthotopic animal model of triple-negative human breast cancer. Oncol Rep. 2012;28:1139–45.CrossRef Jiang J, Thyagarajan-Sahu A, Loganathan J, Eliaz I, Terry C, Sandusky GE, Sliva D. BreastDefend prevents breast-to-lung cancer metastases in an orthotopic animal model of triple-negative human breast cancer. Oncol Rep. 2012;28:1139–45.CrossRef
24.
go back to reference Liu X, Tian S, Liu M, Jian L, Zhao L. Wogonin inhibits the proliferation and invasion, and induces the apoptosis of HepG2 and Bel7402 HCC cells through NFkappaB/Bcl-2, EGFR and EGFR downstream ERK/AKT signaling. Int J Mol Med. 2016;38:1250–256. Liu X, Tian S, Liu M, Jian L, Zhao L. Wogonin inhibits the proliferation and invasion, and induces the apoptosis of HepG2 and Bel7402 HCC cells through NFkappaB/Bcl-2, EGFR and EGFR downstream ERK/AKT signaling. Int J Mol Med. 2016;38:1250–256.
25.
go back to reference Zhao K, Wei L, Hui H, Dai Q, You QD, Guo QL, Lu N. Wogonin suppresses melanoma cell B16-F10 invasion and migration by inhibiting Ras-medicated pathways. PLoS One. 2014;9:e106458.CrossRef Zhao K, Wei L, Hui H, Dai Q, You QD, Guo QL, Lu N. Wogonin suppresses melanoma cell B16-F10 invasion and migration by inhibiting Ras-medicated pathways. PLoS One. 2014;9:e106458.CrossRef
26.
go back to reference Chen P, Lu N, Ling Y, Chen Y, Hui H, Lu Z, Song X, Li Z, You Q, Guo Q. Inhibitory effects of wogonin on the invasion of human breast carcinoma cells by downregulating the expression and activity of matrix metalloproteinase-9. Toxicology. 2011;282:122–8.CrossRef Chen P, Lu N, Ling Y, Chen Y, Hui H, Lu Z, Song X, Li Z, You Q, Guo Q. Inhibitory effects of wogonin on the invasion of human breast carcinoma cells by downregulating the expression and activity of matrix metalloproteinase-9. Toxicology. 2011;282:122–8.CrossRef
27.
go back to reference Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331:1559–64.CrossRef Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331:1559–64.CrossRef
28.
go back to reference Friedl P, Wolf K. Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer. 2003;3:362–74.CrossRef Friedl P, Wolf K. Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer. 2003;3:362–74.CrossRef
29.
go back to reference Castanon I, Baylies MK. A Twist in fate: evolutionary comparison of Twist structure and function. Gene. 2002;287:11–22.CrossRef Castanon I, Baylies MK. A Twist in fate: evolutionary comparison of Twist structure and function. Gene. 2002;287:11–22.CrossRef
30.
go back to reference Sosic D, Richardson JA, Yu K, Ornitz DM, Olson EN. Twist regulates cytokine gene expression through a negative feedback loop that represses NF-kappaB activity. Cell. 2003;112:169–80.CrossRef Sosic D, Richardson JA, Yu K, Ornitz DM, Olson EN. Twist regulates cytokine gene expression through a negative feedback loop that represses NF-kappaB activity. Cell. 2003;112:169–80.CrossRef
31.
go back to reference Huber MA, Azoitei N, Baumann B, Grunert S, Sommer A, Pehamberger H, Kraut N, Beug H, Wirth T. NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest. 2004;114:569–81.CrossRef Huber MA, Azoitei N, Baumann B, Grunert S, Sommer A, Pehamberger H, Kraut N, Beug H, Wirth T. NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest. 2004;114:569–81.CrossRef
32.
go back to reference Borghi A, Verstrepen L, Beyaert R. TRAF2 multitasking in TNF receptor-induced signaling to NF-kappaB, MAP kinases and cell death. Biochem Pharmacol. 2016;116:1–10. Borghi A, Verstrepen L, Beyaert R. TRAF2 multitasking in TNF receptor-induced signaling to NF-kappaB, MAP kinases and cell death. Biochem Pharmacol. 2016;116:1–10.
33.
go back to reference Yi P, Xia W, Wu RC, Lonard DM, Hung MC, O'Malley BW. SRC-3 coactivator regulates cell resistance to cytotoxic stress via TRAF4-mediated p53 destabilization. Genes Dev. 2013;27:274–87.CrossRef Yi P, Xia W, Wu RC, Lonard DM, Hung MC, O'Malley BW. SRC-3 coactivator regulates cell resistance to cytotoxic stress via TRAF4-mediated p53 destabilization. Genes Dev. 2013;27:274–87.CrossRef
34.
go back to reference Zhang L, Zhou F, Garcia de Vinuesa A, de Kruijf EM, Mesker WE, Hui L, Drabsch Y, Li Y, Bauer A, Rousseau A, et al. TRAF4 promotes TGF-beta receptor signaling and drives breast cancer metastasis. Mol Cell. 2013;51:559–72.CrossRef Zhang L, Zhou F, Garcia de Vinuesa A, de Kruijf EM, Mesker WE, Hui L, Drabsch Y, Li Y, Bauer A, Rousseau A, et al. TRAF4 promotes TGF-beta receptor signaling and drives breast cancer metastasis. Mol Cell. 2013;51:559–72.CrossRef
35.
go back to reference Hay ED. An overview of epithelio-mesenchymal transformation. Acta Anat (Basel). 1995;154:8–20.CrossRef Hay ED. An overview of epithelio-mesenchymal transformation. Acta Anat (Basel). 1995;154:8–20.CrossRef
Metadata
Title
Wogonoside inhibits invasion and migration through suppressing TRAF2/4 expression in breast cancer
Authors
Yuyuan Yao
Kai Zhao
Zhou Yu
Haochuan Ren
Li Zhao
Zhiyu Li
Qinglong Guo
Na Lu
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2017
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-017-0574-5

Other articles of this Issue 1/2017

Journal of Experimental & Clinical Cancer Research 1/2017 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine