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.
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.
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.
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.