Disulfiram inhibits epithelial-mesenchymal transition through TGFβ-ERK-Snail pathway independently of Smad4 to

Wenhuan Bu1, Zilin Wang1, Lin Meng1

  • 1Department of Oral Pathology, School and Hospital of Stomatology, Jilin University, 130000 Changchun, People's Republic of China.

Insights

Disulfiram (Dsf) effectively inhibits epithelial-mesenchymal transition (EMT) in oral squamous cell carcinoma (OSCC) cells, regardless of Smad4 mutation status. This suggests Dsf

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Smad4 loss is linked to poor prognosis in oral squamous cell carcinoma (OSCC).
  • Disulfiram (Dsf) exhibits anticancer properties, including the inhibition of epithelial-mesenchymal transition (EMT).
  • The effect of Dsf on Smad4-mutated versus wild-type OSCC and its underlying mechanisms require clarification.

Purpose of the Study:

  • To investigate the efficacy of Disulfiram (Dsf) in inhibiting TGFβ1-induced epithelial-mesenchymal transition (EMT) in both Smad4-mutated and Smad4 wild-type oral squamous cell carcinoma (OSCC) cells.
  • To elucidate the molecular mechanisms by which Dsf affects EMT, focusing on the TGFβ-ERK-Snail pathway.
  • To evaluate the in vivo therapeutic potential of Dsf against OSCC tumor growth and metastasis.

Main Methods:

  • Assessed Dsf's impact on TGFβ1-induced EMT in CAL27 (Smad4 mutation) and SCC25 (Smad4 wild-type) OSCC cells by analyzing morphology, EMT markers, migration, and invasion.
  • Utilized the ERK-pathway inhibitor U0126 to confirm the involvement of the TGFβ-ERK-Snail pathway.
  • Examined Dsf's effects on tumor growth and metastasis in vivo using subcutaneous xenograft and intravenous tumor mouse models.

Main Results:

  • Dsf suppressed TGFβ1-induced EMT, including morphological changes, EMT marker expression, and cell migration/invasion, in both CAL27 and SCC25 cells.
  • Dsf treatment blocked ERK phosphorylation and Snail expression, indicating inhibition of the TGFβ-ERK-Snail pathway.
  • In vivo studies showed Dsf reduced tumor growth and metastasis, with decreased EMT marker expression in tumors.

Conclusions:

  • Disulfiram (Dsf) inhibits EMT in oral squamous cell carcinoma (OSCC) both in vitro and in vivo, independent of Smad4 status.
  • The mechanism involves the suppression of the TGFβ-ERK-Snail pathway.
  • Dsf demonstrates broad-spectrum anticancer potential for clinical application in OSCC treatment.

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