Down-regulation of Glutathione Peroxidase 4 in Oral Cancer Inhibits Tumor Growth Through SREBP1 Signaling

Anticancer Res. 2021 Apr;41(4):1785-1792. doi: 10.21873/anticanres.14944.

Abstract

Background/aim: This study aimed to elucidate the role of glutathione peroxidase 4 (GPX4) on the sterol regulatory element binding proteins (SREBPs)-proliferation pathway in oral cancer cells, and determine its protein expression in oral cancer tissues.

Materials and methods: Quantitative RT-PCR and immunoblot analysis were carried out. Cell viability assay, apoptosis detection assay, immunohistochemistry and GPX4 knockdown were performed.

Results: The levels of both GPX4 mRNA and protein were highest in SAS cells. GPX4 knockdown in SAS cells, a human oral squamous cell carcinoma cell line, using GPX4 siRNA resulted in a reduction in cell number, which appeared to be due to non-apoptotic cell death such as ferroptosis. Furthermore, SREBP was clearly down-regulated by GPX4 knockdown in SAS cells. Immunopositivity for GPX4 was revealed on the membrane of human oral squamous cell carcinoma cells, and this was correlated with p53 immunoreactivity.

Conclusion: GPX4 appears to play an important role in oral cancer proliferation.

Keywords: Glutathione peroxidase 4; SREBP; ferroptosis; human oral squamous cell carcinoma; p53.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Cell Line, Tumor
  • Cell Proliferation*
  • Female
  • Ferroptosis
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Middle Aged
  • Mouth Neoplasms / enzymology*
  • Mouth Neoplasms / genetics
  • Mouth Neoplasms / pathology
  • Phospholipid Hydroperoxide Glutathione Peroxidase / genetics
  • Phospholipid Hydroperoxide Glutathione Peroxidase / metabolism*
  • Signal Transduction
  • Squamous Cell Carcinoma of Head and Neck / enzymology*
  • Squamous Cell Carcinoma of Head and Neck / genetics
  • Squamous Cell Carcinoma of Head and Neck / pathology
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • SREBF1 protein, human
  • Sterol Regulatory Element Binding Protein 1
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Phospholipid Hydroperoxide Glutathione Peroxidase