Journal
CANCER MANAGEMENT AND RESEARCH
Volume 11, Issue -, Pages 3887-3898Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/CMAR.S199912
Keywords
disulfiram; epithelial-mesenchymal transition; Smad4 mutation; oral squamous cell carcinoma
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Funding
- National Key R&D Program of China [2016YFC1102800]
- National Natural Science Foundation of China [881320108011]
- Provincial Industrial Innovation Project of Jilin Province [2016C044-3]
- Jilin Scientific and Technological Development Program [20170101093JC]
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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-mutat ed 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 TGF beta 1-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 TGF beta-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 TGF1-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 TGF beta-ERK-Snail pathway, suggesting the broad-spectrum anticancer potential of Dsf for clinical use against OSCC.
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