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Mitomycin induces alveolar epithelial cell senescence by down-regulating GSK3β signaling

Xiafang Xu1, Xionghua Sun2, Xuelei Wan2

  • 1College of Pharmaceutical Sciences, Soochow University, China; Shaoxing Maternity and Child Health Care Hospital, China.

Toxicology Letters
|October 8, 2021
PubMed

Insights

Mitomycin treatment causes lung damage by inducing alveolar epithelial cell senescence. Glycogen synthase kinase 3 beta (GSK3β) phosphorylation is identified as a key early step in this process.

Area of Science:

  • Cellular Biology
  • Toxicology
  • Pulmonary Medicine

Background:

  • Mitomycin treatment is known to cause pulmonary toxicity.
  • Alveolar epithelial cell senescence plays a critical role in the development of this toxicity.
  • The precise mechanisms underlying mitomycin-induced senescence remain unclear.

Purpose of the Study:

  • To elucidate the mechanism by which mitomycin induces alveolar epithelial cell senescence.
  • To investigate the role of Glycogen synthase kinase 3 beta (GSK3β) phosphorylation in this process.
  • To identify potential therapeutic targets for mitigating mitomycin-induced pulmonary toxicity.

Main Methods:

  • Human alveolar type II-like epithelial cells were treated with varying doses of mitomycin (37.5-300 nM).
  • Investigated the phosphorylation status of GSK3β (S9) and utilized a GSK3β (S9A) mutant.
  • Employed pharmacological inhibition and gene deletion of Akt1, and knockdown of p53.
  • Assessed the effects of baicalein treatment on GSK3β phosphorylation and cell senescence.

Main Results:

  • Mitomycin treatment induced senescence in alveolar epithelial cells and increased GSK3β (S9) phosphorylation.
  • The GSK3β (S9A) mutant reversed mitomycin-induced senescence.
  • Inhibition or deletion of Akt1, and knockdown of p53, suppressed mitomycin-induced senescence.
  • Baicalein treatment reduced GSK3β (S9) phosphorylation and alleviated mitomycin-induced senescence.

Conclusions:

  • GSK3β (S9) phosphorylation is an early signaling event in mitomycin-induced alveolar epithelial cell senescence.
  • The Akt1/GSK3β/p53 pathway is implicated in this process.
  • Targeting GSK3β phosphorylation may offer a strategy to attenuate mitomycin-induced pulmonary toxicity.
Keywords:
BaicaleinCell senescenceGSK3βMitomycinPulmonary toxicity

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