Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Artesunate Inhibits the Proliferation and Migration of Cutaneous Squamous Cell Carcinoma by Regulating the SLC7A11-GPX4 Pathway via the p300-p53 Axis

  • Xinyan Huang (Dermatology Department, The Second Affiliated Hospital Zhejiang University School of Medicine) ;
  • Wenxi Wang (College of Pharmaceutical Science, Zhejiang University of Technology) ;
  • Songzhao Zhang (Department of Clinical Laboratory, The Second Affiliated Hospital Zhejiang University School of Medicine) ;
  • Lili Li (Oncology Department, The Second Affiliated Hospital Zhejiang University School of Medicine) ;
  • Jihui Huang (NanJing University of Chinese Medicine)
  • Received : 2024.08.30
  • Accepted : 2024.12.02
  • Published : 2025.03.01
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Abstract

The incidence of cutaneous squamous cell carcinoma (CSCC) is increasing rapidly. This study discussed the effects of artesunate (ART) on CSCC cell proliferation and migration via the solute carrier family 7 member 11 (SLC7A11)-glutathione peroxidase 4 (GPX4) pathway. MTT assessed cell viability and analyzed the IC50 value (69.26 µM). Accordingly, human CSCC cells (A431) were cultured in vitro, and treated with 70 µM ART, Ferrostatin-1, oe-SLC7A11, and C646, with cell biological behavior assessed. The potential targets of ART were predicted. p53 acetylation and protein stability and ART-p300 binding were examined. Thymusless nude mice were subcutaneously inoculated with A431 cells, and treated with ART and C646. ART-treated A431 cells showed weakened proliferation, migration, lactate dehydrogenase levels, oxidized glutathione/glutathione ratio, reactive oxygen species, malondialdehyde, and active Fe2+ levels, which could be reversed by suppressing ferroptosis. ART promoted p53 acetylation and protein stability and curbed the SLC7A11-GPX4 pathway by targeting p300. ART stimulated ferroptosis via the SLC7A11-GPX4 pathway, thereby repressing CSCC cell proliferation and migration, which were counteracted by p300 inhibition. ART regulated the SLC7A11-GPX4 pathway by up-regulating the p300-p53 axis, thereby hindering tumor growth in vivo. Collectively, ART inhibits CSCC proliferation and migration by modulating the SLC7A11-GPX4 pathway through the p300-p53 axis.

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References

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