Tauroursodeoxycholic acid reduces the invasion of MDA-MB-231 cells by modulating matrix metalloproteinases 7 and 13

Park,Ga‑Young; Han,Yu  Kyeong; Han,Jeong  Yoon; Lee,Chang  Geun

doi:10.3892/ol.2016.4842

Tauroursodeoxycholic acid reduces the invasion of MDA-MB-231 cells by modulating matrix metalloproteinases 7 and 13

Authors:
- Ga‑Young Park
- Yu Kyeong Han
- Jeong Yoon Han
- Chang Geun Lee
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Affiliations: Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan 619‑953, Republic of Korea
Published online on: July 11, 2016 https://doi.org/10.3892/ol.2016.4842
Pages: 2227-2231

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Abstract

Tauroursodeoxycholic acid (TUDCA) is a conjugated form of UDCA that modulates several signaling pathways and acts as a chemical chaperone to relieve endoplasmic reticulum (ER) stress. The present study showed that TUDCA reduced the invasion of the MDA-MB-231 metastatic breast cancer cell line under normoxic and hypoxic conditions using an in vitro invasion assay. Quantitative polymerase chain reaction assay revealed that the reduced invasion following TUDCA treatment was associated with a decreased expression of matrix metalloproteinase (MMP)-7 and -13, which play important roles in invasion and metastasis. Inhibitors and short hairpin RNAs were used to show that the effect of TUDCA in the reduction of invasion appeared to be dependent on the protein kinase RNA‑like ER kinase pathway, a downstream ER stress signaling pathway. Thus, TUDCA is a candidate anti‑metastatic agent to target the ER stress pathway.

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1	Hetz C, Martinon F, Rodriguez D and Glimcher LH: The unfolded protein response: Integrating stress signals through the stress sensor IRE1α. Physiol Rev. 91:1219–1243. 2011. View Article : Google Scholar : PubMed/NCBI
2	Walter P and Ron D: The unfolded protein response: From stress pathway to homeostatic regulation. Science. 334:1081–1086. 2011. View Article : Google Scholar : PubMed/NCBI
3	Lin JH, Walter P and Yen TS: Endoplasmic reticulum stress in disease pathogenesis. Annu Rev Pathol. 3:399–425. 2008. View Article : Google Scholar : PubMed/NCBI
4	Healy SJ, Gorman AM, Mousavi-Shafaei P, Gupta S and Samali A: Targeting the endoplasmic reticulum-stress response as an anticancer strategy. Eur J Pharmacol. 625:234–246. 2009. View Article : Google Scholar : PubMed/NCBI
5	Li Y, Liu H, Huang YY, Pu LJ, Zhang XD, Jiang CC and Jiang ZW: Suppression of endoplasmic reticulum stress-induced invasion and migration of breast cancer cells through the downregulation of heparanase. Int J Mol Med. 31:1234–1242. 2013.PubMed/NCBI
6	Nagelkerke A, Bussink J, Mujcic H, Wouters BG, Lehmann S, Sweep FC and Span PN: Hypoxia stimulates migration of breast cancer cells via the PERK/ATF4/LAMP3-arm of the unfolded protein response. Breast Cancer Res. 15:R22013. View Article : Google Scholar : PubMed/NCBI
7	Chen X, Iliopoulos D, Zhang Q, Tang Q, Greenblatt MB, Hatziapostolou M, Lim E, Tam WL, Ni M, Chen Y, et al: XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway. Nature. 508:103–107. 2014. View Article : Google Scholar : PubMed/NCBI
8	Wimmer R, Hohenester S, Pusl T, Denk GU, Rust C and Beuers U: Tauroursodeoxycholic acid exerts anticholestatic effects by a cooperative cPKC alpha-/PKA-dependent mechanism in rat liver. Gut. 57:1448–1454. 2008. View Article : Google Scholar : PubMed/NCBI
9	Vang S, Longley K, Steer CJ and Low WC: The unexpected uses of urso- and tauroursodeoxycholic acid in the treatment of non-liver diseases. Glob Adv Health Med. 3:58–69. 2014. View Article : Google Scholar : PubMed/NCBI
10	Han YK, Lee JH, Park GY, Chun SH, Han JY, Kim SD, Lee J, Lee CW, Yang K and Lee CG: A possible usage of a CDK4 inhibitor for breast cancer stem cell-targeted therapy. Biochem Biophys Res Commun. 430:1329–1333. 2013. View Article : Google Scholar : PubMed/NCBI
11	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
12	Yadav L, Puri N, Rastogi V, Satpute P, Ahmad R and Kaur G: Matrix metalloproteinases and cancer-roles in threat and therapy. Asian Pac J Cancer Prev. 15:1085–1091. 2014. View Article : Google Scholar : PubMed/NCBI
13	Ye Y, Zhou X, Li X, Tang Y, Sun Y and Fang J: Inhibition of epidermal growth factor receptor signaling prohibits metastasis of gastric cancer via downregulation of MMP7 and MMP13. Tumour Biol. 35:10891–10896. 2014. View Article : Google Scholar : PubMed/NCBI
14	Zhang J, Wang S, Lu L and Wei G: MiR99a modulates MMP7 and MMP13 to regulate invasiveness of Kaposi's sarcoma. Tumour Biol. 35:12567–12573. 2014. View Article : Google Scholar : PubMed/NCBI
15	Chia SK, Wykoff CC, Watson PH, Han C, Leek RD, Pastorek J, Gatter KC, Ratcliffe P and Harris AL: Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. J Clin Oncol. 19:3660–3668. 2001.PubMed/NCBI
16	Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U and Vaupel P: Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res. 56:4509–4515. 1996.PubMed/NCBI
17	Rademakers SE, Span PN, Kaanders JH, Sweep FC, van der Kogel AJ and Bussink J: Molecular aspects of tumour hypoxia. Mol Oncol. 2:41–53. 2008. View Article : Google Scholar : PubMed/NCBI
18	Liu Y, László C, Liu Y, Liu W, Chen X, Evans SC and Wu S: Regulation of G(1) arrest and apoptosis in hypoxia by PERK and GCN2-mediated eIF2alpha phosphorylation. Neoplasia. 12:61–68. 2010. View Article : Google Scholar : PubMed/NCBI
19	Rouschop KM, Dubois LJ, Keulers TG, van den Beucken T, Lambin P, Bussink J, van der Kogel AJ, Koritzinsky M and Wouters BG: PERK/eIF2α signaling protects therapy resistant hypoxic cells through induction of glutathione synthesis and protection against ROS. Proc Natl Acad Sci USA. 110:4622–4627. 2013. View Article : Google Scholar : PubMed/NCBI