Synergistic effect of targeting dishevelled‑3 and the epidermal growth factor receptor‑tyrosine kinase inhibitor on mesothelioma cells in vitro

Moriyama,Gaku; Tanigawa,Maya; Sakai,Kosuke; Hirata,Yusuke; Kikuchi,Satoshi; Saito,Yuriko; Kyoyama,Hiroyuki; Matsuda,Kuniko; Seike,Masahiro; Gemma,Akihiko; Uematsu,Kazutsugu

doi:10.3892/ol.2017.7382

Synergistic effect of targeting dishevelled‑3 and the epidermal growth factor receptor‑tyrosine kinase inhibitor on mesothelioma cells in vitro

Authors:
- Gaku Moriyama
- Maya Tanigawa
- Kosuke Sakai
- Yusuke Hirata
- Satoshi Kikuchi
- Yuriko Saito
- Hiroyuki Kyoyama
- Kuniko Matsuda
- Masahiro Seike
- Akihiko Gemma
- Kazutsugu Uematsu
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Affiliations: Department of Pulmonary Medicine, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama 350‑8550, Japan, Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo 113‑8603, Japan
Published online on: November 9, 2017 https://doi.org/10.3892/ol.2017.7382
Pages: 833-838
Copyright: © Moriyama et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

It was previously revealed that Wnt signaling is activated in mesothelioma cells. Although epidermal growth factor receptor (EGFR) is expressed in mesothelioma cells, EGFR‑tyrosine kinase inhibitors (TKIs) are not effective for mesothelioma treatment. However, in non‑small cell lung cancer, the blocking of Wnt signaling has been identified to enhance the anticancer effect of EGFR‑TKIs. To confirm the anticancer effect of blocking Wnt signaling in combination with EGFR‑TKI treatment in mesothelioma, the present study evaluated the effect of simultaneous suppression of human dishevelled‑3 (Dvl‑3) expression with Dvl‑3 small interfering RNA (siRNA) and of EGFR inhibition with gefitinib on mesothelioma cell viability. Mesothelioma cell lines with and without β‑catenin gene expression were transfected with Dvl‑3 siRNA and were cultured with gefitinib, and cell viability, colony formation and cell cycle analyses were performed. Dvl‑3 siRNA downregulated the expression of Dvl‑3 in mesothelioma cells. The combination of Dvl‑3 siRNA with gefitinib acted synergistically to induce concomitant suppression of cell viability and colony formation, suggesting that inhibition of Wnt signaling by downregulating Dvl‑3 with siRNA and inhibiting EGFR with gefitinib leads to significant antitumor effects.

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1	Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, et al: Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 21:2636–2644. 2003. View Article : Google Scholar : PubMed/NCBI
2	Zhan T, Rindtorff N and Boutros M: Wnt signaling in cancer. Oncogene. 36:1461–1473. 2017. View Article : Google Scholar : PubMed/NCBI
3	Uematsu K, Kanazawa S, You L, He B, Xu Z, Li K, Peterlin BM, McCormick F and Jablons DM: Wnt pathway activation in mesothelioma: Evidence of dishevelled overexpression and transcriptional activity of β-catenin. Cancer Res. 63:4547–4551. 2003.PubMed/NCBI
4	Uematsu K, He B, You L, Xu Z, McCormick F and Jablons DM: Activation of the Wnt pathway in non small cell lung cancer: Evidence of dishevelled overexpression. Oncogene. 22:7218–7221. 2003. View Article : Google Scholar : PubMed/NCBI
5	He B, You L, Uematsu K, Xu Z, Lee AY, Matsangou M, McCormick F and Jablons DM: A monoclonal antibody against Wnt-1 induces apoptosis in human cancer cells. Neoplasia. 6:7–14. 2004. View Article : Google Scholar : PubMed/NCBI
6	You L, He B, Xu Z, Uematsu K, Mazieres J, Fujii N, Mikami I, Reguart N, McIntosh JK, Kashani-Sabet M, et al: An anti-Wnt-2 monoclonal antibody induces apoptosis in malignant melanoma cells and inhibits tumor growth. Cancer Res. 64:5385–5389. 2004. View Article : Google Scholar : PubMed/NCBI
7	Fujii N, You L, Xu Z, Uematsu K, Shan J, He B, Mikami I, Edmondson LR, Neale G, Zheng J, et al: An antagonist of dishevelled protein-protein interaction suppresses β-catenin-dependent tumor cell growth. Cancer Res. 67:573–579. 2007. View Article : Google Scholar : PubMed/NCBI
8	You L, He B, Uematsu K, Xu Z, Mazieres J, Lee A, McCormick F and Jablons DM: Inhibition of Wnt-1 signaling induces apoptosis in β-catenin-deficient mesothelioma cells. Cancer Res. 64:3474–3478. 2004. View Article : Google Scholar : PubMed/NCBI
9	Stewart DJ: Wnt signaling pathway in non-small cell lung cancer. J Natl Cancer Inst. 106:djt3562014. View Article : Google Scholar : PubMed/NCBI
10	Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 350:2129–2139. 2004. View Article : Google Scholar : PubMed/NCBI
11	Dazzi H, Hasleton PS, Thatcher N, Wilkes S, Swindell R and Chatterjee AK: Malignant pleural mesothelioma and epidermal growth factor receptor (EGF-R). Relationship of EGF-R with histology and survival using fixed paraffin embedded tissue and the F4, monoclonal antibody. Br J Cancer. 61:924–926. 1990. View Article : Google Scholar : PubMed/NCBI
12	Govindan R, Kratzke RA, Herndon JE II, Niehans GA, Vollmer R, Watson D, Green MR and Kindler HL; Cancer and Leukemia Group B (CALGB 30101), : Gefitinib in patients with malignant mesothelioma: A phase II study by the cancer and leukemia group B. Clin Cancer Res. 11:2300–2304. 2005. View Article : Google Scholar : PubMed/NCBI
13	Casás-Selves M, Kim J, Zhang Z, Helfrich BA, Gao D, Porter CC, Scarborough HA, Bunn PA Jr, Chan DC, Tan AC and DeGregori J: Tankyrase and the canonical Wnt pathway protect lung cancer cells from EGFR inhibition. Cancer Res. 72:4154–4164. 2012. View Article : Google Scholar : PubMed/NCBI
14	Fong JT, Jacobs RJ, Moravec DN, Uppada SB, Botting GM, Nlend M and Puri N: Alternative signaling pathways as potential therapeutic targets for overcoming EGFR and c-Met inhibitor resistance in non-small cell lung cancer. PLoS One. 8:e783982013. View Article : Google Scholar : PubMed/NCBI
15	Togashi Y, Hayashi H, Terashima M, de Velasco MA, Sakai K, Fujita Y, Tomida S, Nakagawa K and Nishio K: Inhibition of β-catenin enhances the anticancer effect of irreversible EGFR-TKI in EGFR-mutated non-small-cell lung cancer with a T790M mutation. J Thorac Oncol. 10:93–101. 2015. View Article : Google Scholar : PubMed/NCBI
16	Zhang Y, Zhang X, Huang J and Dong Q: Wnt signaling regulation of stem-like properties in human lung adenocarcinoma cell lines. Med Oncol. 32:1572015. View Article : Google Scholar : PubMed/NCBI
17	Uematsu K, Seki N, Seto T, Isoe C, Tsukamoto H, Mikami I, You L, He B, Xu Z, Jablons DM and Eguchi K: Targeting the wnt signaling pathway with dishevelled and cisplatin synergistically suppresses mesothelioma cell growth. Anticancer Res. 27:4239–4242. 2007.PubMed/NCBI
18	Jänne PA, Taffaro ML, Salgia R and Johnson BE: Inhibition of epidermal growth factor receptor signaling in malignant pleural mesothelioma. Cancer Res. 62:5242–5247. 2002.PubMed/NCBI
19	Nutt JE, O'Toole K, Gonzalez D and Lunec J: Growth inhibition by tyrosine kinase inhibitors in mesothelioma cell lines. Eur J Cancer. 45:1684–1691. 2009. View Article : Google Scholar : PubMed/NCBI
20	Zheng H, Saito H, Masuda S, Yang X and Takano Y: Phosphorylated GSK3beta-ser9 and EGFR are good prognostic factors for lung carcinomas. Anticancer Res. 27:3561–3569. 2007.PubMed/NCBI
21	McCubrey JA, Rakus D, Gizak A, Steelman LS, Abrams SL, Lertpiriyapong K, Fitzgerald TL, Yang LV, Montalto G, Cervello M, et al: Effects of mutations in Wnt/β-catenin, hedgehog, notch and PI3K pathways on GSK-3 activity-diverse effects on cell growth, metabolism and cancer. Biochim Biophys Acta. 1863:2942–2976. 2016. View Article : Google Scholar : PubMed/NCBI
22	Paul I, Bhattacharya S, Chatterjee A and Ghosh MK: Current understanding on EGFR and Wnt/β-catenin signaling in glioma and their possible crosstalk. Genes Cancer. 4:427–446. 2013. View Article : Google Scholar : PubMed/NCBI
23	Hu T and Li C: Convergence between Wnt-β-catenin and EGFR signaling in cancer. Mol Cancer. 9:2362010. View Article : Google Scholar : PubMed/NCBI
24	Gao C and Chen YG: Dishevelled: The hub of Wnt signaling. Cell Signal. 22:717–727. 2010. View Article : Google Scholar : PubMed/NCBI
25	Zhao H, Zhao Y, Jiang G, Zhang X, Zhang Y, Dong Q, Luan L, Papavassiliou P and Wang E: Dishevelled-3 activates p65 to upregulate p120-catenin transcription via a p38-dependent pathway in non-small cell lung cancer. Mol Carcinog. 54:E112–E121. 2015. View Article : Google Scholar : PubMed/NCBI
26	Zhang X, Yu X, Jiang G, Miao Y, Wang L, Zhang Y, Liu Y, Fan C, Lin X, Dong Q, et al: Cytosolic TMEM88 promotes invasion and metastasis in lung cancer cells by binding DVLs. Cancer Res. 75:4527–4537. 2015. View Article : Google Scholar : PubMed/NCBI