Esophageal cancer stem-like cells resist ferroptosis-induced cell death by active hsp27-gpx4 pathway

Chen Chi Liu, Hsin Hsien Li, Jiun Han Lin, Ming Chen Chiang, Tien Wei Hsu, Anna Fen Yau Li, David Hung Tsang Yen, Han Shui Hsu*, Shih Chieh Hung

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Cancer stem cells (CSCs), a subpopulation of cancer cells responsible for tumor initiation and treatment failure, are more susceptible to ferroptosis-inducing agents than bulk cancer cells. However, regulatory pathways controlling ferroptosis, which can selectively induce CSC death, are not fully understood. Here, we demonstrate that the CSCs of esophageal squamous carcinoma cells enriched by spheroid culture have increased intracellular iron levels and lipid peroxidation, thereby increasing exposure to several products of lipid peroxidation, such as MDA and 4-HNE. However, CSCs do not reduce cell viability until glutathione is depleted by erastin treatment. Mechanistic studies revealed that damage from elevated lipid peroxidation is avoided through the activation of Hsp27, which upregulates GPX4 and thereby rescues CSCs from ferroptosis-induced cell death. Our results also revealed a correlation between phospho-Hsp27 and GPX4 expression levels and poor prognosis in patients with esophageal cancer. Together, these data indicate that targeting Hsp27 or GPX4 to block this intrinsic protective mechanism against ferroptosis is a potential treatment strategy for eradicating CSC in esophageal squamous cell carcinoma.

Original languageEnglish
Article number48
JournalBiomolecules
Volume12
Issue number1
DOIs
StatePublished - Jan 2022

Keywords

  • Cancer stem cells
  • Esophageal cancer
  • Ferroptosis
  • GPX4
  • Hsp27

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