Baicalein Inhibits Epithelial to Mesenchymal Transition Via Downregulation of Cyr61 and LOXL-2 in MDA-MB231 Breast Cancer Cells

Overview

Journal Mol Cells

Publisher Elsevier

Specialties Cell Biology
Molecular Biology

Date 2016 Dec 24

PMID 28008161

Citations 10

Authors

Linh Thi Thao Nguyen

Yeon Woo Song

Somi Kim Cho

Affiliations

Soon will be listed here.

Abstract

Epithelial-mesenchymal transition (EMT) is a critical step in the acquisition of the migratory and invasive capabilities associated with metastatic competence. Cysteine-rich protein 61 (CCN1/Cyr61) has been implicated as an important mediator in the proliferation and metastasis of breast cancer. Hence, Cyr61 and associated pathways are attractive targets for therapeutic interventions directed against the EMT. In the present study, we report that baicalein significantly inhibits the expression of Cyr61 and migration and invasion of MDA-MB231 human breast cancer cells. Exposure to baicalein led to increased E-cadherin expression, possibly due to the ubiquitination of Snail and Slug, which was mediated by the Cyr61/Akt/glycogen synthase kinase 3β (GSK3β) pathway. Further analysis revealed that baicalein inhibited the expression of lysyl oxidase like-2 (LOXL-2), which is a functional collaborator of Snail and Slug, and subsequently attenuated the direct interaction between LOXL-2 and Snail or Slug, thereby enhancing GSK3β-dependent Snail and Slug degradation. Our findings provide new insights into the antimetastatic mechanism of baicalein and may contribute to its beneficial use in breast cancer therapies.

Citing Articles

Baicalein blocked gastric cancer cell proliferation and invasion through modulated platelet type 12-lipoxygenase.

Ye J, Qiao D, Zhang Y, Piao Y, Jin J Iran J Basic Med Sci. 2024; 27(12):1574-1582.

PMID: 39539438 PMC: 11556770. DOI: 10.22038/ijbms.2024.80479.17422.

CYR61 promotes colorectal carcinoma progression via activating epithelial-mesenchymal transition.

Rasool S, Al Ismaeel Q, Arif S Am J Cancer Res. 2023; 13(10):4872-4887.

PMID: 37970355 PMC: 10636662.

Inhibition of Increased Invasiveness of Breast Cancer Cells With Acquired Tamoxifen Resistance by Suppression of CYR61.

Bauerschmitz G, Huchel S, Gallwas J, Grundker C Cancer Genomics Proteomics. 2023; 20(6):531-538.

PMID: 37889058 PMC: 10614060. DOI: 10.21873/cgp.20403.

Anti-Cancer Potential of Phytochemicals: The Regulation of the Epithelial-Mesenchymal Transition.

Liu S, Li L, Ren D Molecules. 2023; 28(13).

PMID: 37446730 PMC: 10343761. DOI: 10.3390/molecules28135069.

The interaction between cucurbit[8]uril and baicalein and the effect on baicalein properties.

Zhang X, Xie J, Xu Z, Tao Z, Zhang Q Beilstein J Org Chem. 2020; 16:71-77.

PMID: 31976018 PMC: 6964663. DOI: 10.3762/bjoc.16.9.

References

Wu B, Li J, Huang D, Wang W, Chen Y, Liao Y . Baicalein mediates inhibition of migration and invasiveness of skin carcinoma through Ezrin in A431 cells. BMC Cancer. 2011; 11:527. PMC: 3260329. DOI: 10.1186/1471-2407-11-527. View

Bakin A, Tomlinson A, Bhowmick N, Moses H, Arteaga C . Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem. 2000; 275(47):36803-10. DOI: 10.1074/jbc.M005912200. View

Hayashi K, Fong K, Mercier F, Boyd C, Csiszar K, Hayashi M . Comparative immunocytochemical localization of lysyl oxidase (LOX) and the lysyl oxidase-like (LOXL) proteins: changes in the expression of LOXL during development and growth of mouse tissues. J Mol Histol. 2004; 35(8-9):845-55. DOI: 10.1007/s10735-004-2340-1. View

Po L, Chen Z, Tsang D, Leung L . Baicalein and genistein display differential actions on estrogen receptor (ER) transactivation and apoptosis in MCF-7 cells. Cancer Lett. 2002; 187(1-2):33-40. DOI: 10.1016/s0304-3835(02)00355-5. View

Chen C, Huang L, Huang C, Lin C, Lee Y, Lu F . Baicalein, a novel apoptotic agent for hepatoma cell lines: a potential medicine for hepatoma. Nutr Cancer. 2001; 38(2):287-95. DOI: 10.1207/S15327914NC382_19. View

Peinado H, Iglesias-de la Cruz M, Olmeda D, Csiszar K, Fong K, Vega S . A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression. EMBO J. 2005; 24(19):3446-58. PMC: 1276164. DOI: 10.1038/sj.emboj.7600781. View

Tran T, Krishnamoorthy K, Cho S, Kim S . Inhibitory Effect of Zinc Sulfide Nanoparticles Towards Breast Cancer Stem Cell Migration and Invasion. J Biomed Nanotechnol. 2016; 12(2):329-36. DOI: 10.1166/jbn.2016.2187. View

Babic A, Kireeva M, Kolesnikova T, Lau L . CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth. Proc Natl Acad Sci U S A. 1998; 95(11):6355-60. PMC: 27701. DOI: 10.1073/pnas.95.11.6355. View

Xie D, Nakachi K, Wang H, Elashoff R, Koeffler H . Elevated levels of connective tissue growth factor, WISP-1, and CYR61 in primary breast cancers associated with more advanced features. Cancer Res. 2001; 61(24):8917-23. View

10.

Zhou B, Deng J, Xia W, Xu J, Li Y, Gunduz M . Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol. 2004; 6(10):931-40. DOI: 10.1038/ncb1173. View

11.

Haque I, Mehta S, Majumder M, Dhar K, De A, McGregor D . Cyr61/CCN1 signaling is critical for epithelial-mesenchymal transition and stemness and promotes pancreatic carcinogenesis. Mol Cancer. 2011; 10:8. PMC: 3027193. DOI: 10.1186/1476-4598-10-8. View

12.

Peinado H, Moreno-Bueno G, Hardisson D, Perez-Gomez E, Santos V, Mendiola M . Lysyl oxidase-like 2 as a new poor prognosis marker of squamous cell carcinomas. Cancer Res. 2008; 68(12):4541-50. DOI: 10.1158/0008-5472.CAN-07-6345. View

13.

Tan T, Yang W, Lin Y, Hsu S, Li T, Kao S . Cyr61 increases migration and MMP-13 expression via alphavbeta3 integrin, FAK, ERK and AP-1-dependent pathway in human chondrosarcoma cells. Carcinogenesis. 2009; 30(2):258-68. DOI: 10.1093/carcin/bgn284. View

14.

Chung H, Choi H, Seo E, Kang D, Oh E . Baicalin and baicalein inhibit transforming growth factor-β1-mediated epithelial-mesenchymal transition in human breast epithelial cells. Biochem Biophys Res Commun. 2015; 458(3):707-713. DOI: 10.1016/j.bbrc.2015.02.032. View

15.

Barker H, Chang J, Cox T, Lang G, Bird D, Nicolau M . LOXL2-mediated matrix remodeling in metastasis and mammary gland involution. Cancer Res. 2011; 71(5):1561-72. PMC: 3842018. DOI: 10.1158/0008-5472.CAN-10-2868. View

16.

Doble B, Woodgett J . Role of glycogen synthase kinase-3 in cell fate and epithelial-mesenchymal transitions. Cells Tissues Organs. 2007; 185(1-3):73-84. DOI: 10.1159/000101306. View

17.

Lin M, Zuon C, Chang C, Chen S, Chen C, Lin B . Cyr61 induces gastric cancer cell motility/invasion via activation of the integrin/nuclear factor-kappaB/cyclooxygenase-2 signaling pathway. Clin Cancer Res. 2005; 11(16):5809-20. DOI: 10.1158/1078-0432.CCR-04-2639. View

18.

Chuang J, Yu N, Chiang I, Lai C, Lin C, Tang C . Cyr61 increases matrix metalloproteinase-3 expression and cell motility in human oral squamous cell carcinoma cells. J Cell Biochem. 2012; 113(6):1977-86. DOI: 10.1002/jcb.24066. View

19.

Grille S, Bellacosa A, Upson J, Klein-Szanto A, van Roy F, Lee-Kwon W . The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res. 2003; 63(9):2172-8. View

20.

Moreno-Bueno G, Salvador F, Martin A, Floristan A, Cuevas E, Santos V . Lysyl oxidase-like 2 (LOXL2), a new regulator of cell polarity required for metastatic dissemination of basal-like breast carcinomas. EMBO Mol Med. 2011; 3(9):528-44. PMC: 3377095. DOI: 10.1002/emmm.201100156. View