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Disulfiram inhibits epithelial–mesenchymal transition through TGFβ–ERK–Snail pathway independently of Smad4 to decrease oral squamous cell carcinoma metastasis

Authors Bu W, Wang Z, Meng L, Li X, Liu X, Chen Y, Xin Y, Li B, Sun H

Received 30 December 2018

Accepted for publication 7 April 2019

Published 1 May 2019 Volume 2019:11 Pages 3887—3898

DOI https://doi.org/10.2147/CMAR.S199912

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 3

Editor who approved publication: Professor Nakshatri


Wenhuan Bu,1* Zilin Wang,1,* Lin Meng,1,* Xing Li,2 Xinchen Liu,1 Yumeng Chen,1 Ying Xin,3 Baoquan Li,4 Hongchen Sun1

1
Department of Oral Pathology, School and Hospital of Stomatology, Jilin University, 130000 Changchun, People’s Republic of China; 2School and Hospital of Stomatology, China Medical University, 110000 Shenyang, People’s Republic of China; 3Department of Oral Pathology, Hospital of Stomatology, Xi’an Jiaotong University, Xi’an, 710000, People’s Republic of China; 4Department of Temporomandibular Joint, School and Hospital of Stomatology, Jilin University, 130000 Changchun, People’s Republic of China

*These authors contributed equally to this work
Purpose: Smad4 loss is highly related to poor prognosis and decreased patient survival in oral squamous cell carcinoma (OSCC), suggesting that agents that target both Smad4-mutated and Smad4 wild-type cells could treat OSCC more effectively. Disulfiram (Dsf) has anticancer activity through a variety of mechanisms, including inhibition of epithelial–mesenchymal transition (EMT). It remains unclear whether Dsf has the same effect on Smad4-mutated and Smad4 wild-type OSCC or not and what mechanism is involved.
Methods: Effect of Dsf on TGFβ1-induced EMT in CAL27 (Smad4 mutation) and SCC25 (Smad4 wild-type) cells were evaluated through analyzing changes in morphology, expression of EMT markers, and migration and invasion of cells. The ERK-pathway inhibitor U0126 was used to confirm TGFβ–ERK–Snail pathway–mediated cell behavior. Dsf’s effects on tumor growth and metastasis in vivo were examined through a subcutaneous xenograft mouse model and an intravenous tumor mouse model.
Results: Dsf inhibited TGFβ1-induced EMT through suppression of morphological change, EMT-marker expression, and cell migration and invasion in both CAL27 and SCC25. Phosphorylation of ERK and expression of Snail were blocked by Dsf treatment. Like Dsf, U0126 had a similar effect on EMT of CAL27 and SCC25. Dsf also reduced tumor growth and metastasis in vivo, accompanied by decreased expression of EMT markers in tumors.
Conclusion: These results indicated that Dsf inhibited EMT of OSCC in vitro and in vivo independently of Smad4 through suppression of the TGFβ–ERK–Snail pathway, suggesting the broad-spectrum anticancer potential of Dsf for clinical use against OSCC.

Keywords: disulfiram, epithelial–mesenchymal transition, Smad4 mutation, oral squamous cell carcinoma

Corrigendum for this paper has been published

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