Honokiol inhibits U87MG human glioblastoma cell invasion through endothelial cells by regulating membrane permeability and the epithelial-mesenchymal transition

Joo,Young  Nak; Eun,So  Young; Park,Sang  Won; Lee,Jae  Heun; Chang,Ki  Churl; Kim,Hye  Jung

doi:10.3892/ijo.2013.2178

Honokiol inhibits U87MG human glioblastoma cell invasion through endothelial cells by regulating membrane permeability and the epithelial-mesenchymal transition

Authors:
- Young Nak Joo
- So Young Eun
- Sang Won Park
- Jae Heun Lee
- Ki Churl Chang
- Hye Jung Kim
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Affiliations: Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea
Published online on: November 15, 2013 https://doi.org/10.3892/ijo.2013.2178
Pages: 187-194

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Abstract

Glioblastoma is one of the most lethal and prevalent malignant human brain tumors, with aggressive proliferation and highly invasive properties. There is still no effective cure for patients with glioblastoma. Honokiol, derived from Magnolia officinalis, can cross the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB), making it a strong candidate for an effective drug for the treatment of brain tumors, including glioblastoma. In our previous study, we demonstrated that honokiol effectively induced apoptotic cell death in glioblastoma. Metastasis poses the largest problem to cancer treatment and is the primary cause of death in cancer patients. Thus, in this study, we investigated the effect of honokiol on the cell invasion process of U87MG human glioblastoma cells through brain microvascular endothelial cells (BMECs) and its possible mechanisms. Honokiol dose-dependently inhibited TNF-α-induced VCAM-1 expression in BMECs and adhesion of U87MG to BMECs. Moreover, honokiol effectively blocked U87MG invasion through BMEC-Matrigel-coated transwell membranes. Increased phosphorylation of VE-cadherin and membrane permeability by TNF-α were suppressed by honokiol in BMECs. Furthermore, we investigated the effect of honokiol on the epithelial-mesenchymal transition (EMT) in U87MG cells. Honokiol reduced the expression levels of Snail, N-cadherin and β-catenin, which are mesenchymal markers, but increased E-cadherin, an epithelial marker. In conclusion, these results suggest that honokiol inhibits metastasis by targeting the interaction between U87MG and BMECs, regulating the adhesion of U87MG to BMECs by inhibiting VCAM-1, and regulating the invasion of U87MG through BMECs by reducing membrane permeability and EMT processes of U87MG cells.

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1.	Nakada M, Nakada S, Demuth T, Tran NL, Hoelzinger DB and Berens ME: Molecular targets of glioma invasion. Cell Mol Life Sci. 64:458–478. 2007. View Article : Google Scholar : PubMed/NCBI
2.	Clark MJ, Homer N, O’Connor BD, Chen Z, Eskin A, Lee H, Merriman B and Nelson SF: U87MG decoded: the genomic sequence of a cytogenetically aberrant human cancer cell line. PLoS Genet. 6:e10008322010. View Article : Google Scholar : PubMed/NCBI
3.	Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E and Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005. View Article : Google Scholar : PubMed/NCBI
4.	Fox SB, Turner GD, Gatter KC and Harris AL: The increased expression of adhesion molecules ICAM-3, E-selectin and P-selectins on breast cancer endothelium. J Pathol. 177:369–376. 1995. View Article : Google Scholar : PubMed/NCBI
5.	Nizamutdinova IT, Lee GW, Lee JS, Cho MK, Son KH, Jeon SJ, Kang SS, Kim YS, Lee JH, Seo HG, Chang KC and Kim HJ: Tanshinone I suppresses growth and invasion of human breast cancer cells, MDA-MB-231, through regulation of adhesion molecules. Carcinogenesis. 29:1885–1892. 2008. View Article : Google Scholar : PubMed/NCBI
6.	Christiansen I, Sundstrom C and Totterman TH: Elevated serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) closely reflect tumour burden in chronic B-lymphocytic leukaemia. Br J Haematol. 103:1129–1137. 1998. View Article : Google Scholar : PubMed/NCBI
7.	Maeda K, Kang SM, Sawada T, Nishiguchi Y, Yashiro M, Ogawa Y, Ohira M, Ishikawa T, Hirakawa YS and Chung K: Expression of intercellular adhesion molecule-1 and prognosis in colorectal cancer. Oncol Rep. 9:511–514. 2002.PubMed/NCBI
8.	Becker JC, Dummer R, Hartmann AA, Burg G and Schmidt RE: Shedding of ICAM-1 from human melanoma cell lines induced by IFN-gamma and tumor necrosis factor-alpha. Functional consequences on cell-mediated cytotoxicity. J Immunol. 147:4398–4401. 1991.
9.	Osborn L, Hession C, Tizard R, Vassallo C, Luhowskyj S, Chi-Rosso G and Lobb R: Direct expression cloning of vascular cell adhesion molecule-1, a cytokine-induced endothelial protein that binds to lymphocytes. Cell. 59:1203–1211. 1989. View Article : Google Scholar : PubMed/NCBI
10.	Kim HJ, Tsoy I, Park JM, Chung JI, Shin SC and Chang KC: Anthocyanins from soybean seed coat inhibit the expression of TNF-α-induced genes associated with ischemia/reperfusion in endothelial cell by NF-κB-dependent pathway and reduce rat myocardial damages incurred by ischemia and reperfusion in vivo. FEBS Lett. 580:1391–1397. 2006.PubMed/NCBI
11.	Nizamutdinova IT, Oh HM, Min YN, Park SH, Lee MJ, Kim JS, Yean MH, Kang SS, Kim YS, Chang KC and Kim HJ: Paeonol suppresses intercellular adhesion molecule-1 expression in tumor necrosis factor-α-stimulated human umbilical vein ECs by blocking p38, ERK and nuclear factor-κB signaling pathways. Int Immunopharmacol. 7:343–350. 2007.PubMed/NCBI
12.	Thompson EW and Price JT: Mechanisms of tumour invasion and metastasis: emerging targets for therapy. Expert Opin Ther Targets. 6:217–233. 2002. View Article : Google Scholar : PubMed/NCBI
13.	Balkwill F and Mantovani A: Inflammation and cancer: back to Virchow? Lancet. 357:539–545. 2001. View Article : Google Scholar : PubMed/NCBI
14.	Cavallaro U and Christofori G: Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer. 4:118–132. 2004. View Article : Google Scholar : PubMed/NCBI
15.	Liou KT, Shen YC, Chen CF, Tsao CM and Tsai SK: Honokiol protects rat brain from focal cerebral ischemia-reperfusion injury by inhibiting neutrophil infiltration and reactive oxygen species production. Brain Res. 992:159–166. 2003. View Article : Google Scholar : PubMed/NCBI
16.	Hibasami H, Achiwa Y, Katsuzaki H, Imai K, Yoshioka K, Nakanishi K, Ishii Y, Hasegawa M and Komiya T: Honokiol induces apoptosis in human lymphoid leukemia molt 4B cells. Int J Mol Med. 2:671–673. 1998.PubMed/NCBI
17.	Yang SE, Hsieh MT, Tsai TH and Hsu SL: Downmodulation of Bcl-XL, release of cytochrome c and sequential activation of caspases during honokiol induced apoptosis in human squamous lung cancer CH27 cells. Biochem Pharmacol. 63:1641–1651. 2002. View Article : Google Scholar : PubMed/NCBI
18.	Wang T, Chen F, Chen Z, Wu YF, Xu XL, Zheng S and Hu X: Honokiol induces apoptosis through p53-independent pathway in human colorectal cell line RKO. World J Gastroenterol. 10:2205–2208. 2004.PubMed/NCBI
19.	Hirano T, Gotoh M and Oka K: Natural flavonoids and lignans are potent cytostatic agents against human leukemic HL-60 cells. Life Sci. 55:1061–1069. 1994. View Article : Google Scholar : PubMed/NCBI
20.	Crane C, Panner A, Pieper RO, Arbiser J and Parsa AT: Honokiol-mediated inhibition of PI3K/mTOR pathway: a potential strategy to overcome immunoresistance in glioma, breast, and prostate carcinoma without impacting T cell function. J Immunother. 32:585–592. 2009. View Article : Google Scholar
21.	Wang X, Duan X, Yang G, Zhang X, Deng L, Zheng H, Deng C, Wen J, Wang N, Peng C, Zhao X, Wei Y and Chen L: Honokiol crosses BBB and BCSFB, and inhibits brain tumor growth in rat 9L intracerebral gliosarcoma model and human U251 xenograft glioma model. PLoS One. 6:e184902011. View Article : Google Scholar : PubMed/NCBI
22.	Jeong JJ, Lee JH, Chang KC and Kim HJ: Honokiol exerts an anticancer effect in T98G human glioblastoma cells through the induction of apoptosis and the regulation of adhesion molecules. Int J Oncol. 41:1358–1364. 2012.PubMed/NCBI
23.	Ponten J and Macintyre EH: Long term culture of normal and neoplastic human glia. Acta Pathol Microbiol Scand. 74:465–486. 1968. View Article : Google Scholar : PubMed/NCBI
24.	Klemke M, Weschenfelder T, Konstandin MH and Samstag Y: High affinity interaction of integrin alpha4beta1 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1) enhances migration of human melanoma cells across activated endothelial cell layers. J Cell Physiol. 212:368–374. 2007. View Article : Google Scholar
25.	Wu TC: The role of vascular cell adhesion molecule-1 in tumor immune evasion. Cancer Res. 67:6003–6006. 2007. View Article : Google Scholar : PubMed/NCBI
26.	Davis FG, Freels S, Grutsch J, Barlas S and Brem S: Survival rates in patients with primary malignant brain tumors stratified by patient age and tumor histological type: analysis based on surveillance, epidemiology and end results (SEER) data, 1973–1991. J Neurosurg. 88:11998.PubMed/NCBI
27.	Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J and Dirks PB: Identification of a cancer stem cell in human brain tumors. Cancer Res. 63:5821–5828. 2003.PubMed/NCBI
28.	Moon SH and Park KS: Enrichment of cancer stem cell of glioblastoma by neurosphere formation. Tissue Eng Regenerative Med. 9:40–47. 2012.
29.	Dejana E, Orsenigo F and Lampugnani MG: The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci. 121:2115–2122. 2008. View Article : Google Scholar : PubMed/NCBI