期刊
BIOMOLECULES
卷 12, 期 1, 页码 -出版社
MDPI
DOI: 10.3390/biom12010048
关键词
esophageal cancer; cancer stem cells; ferroptosis; Hsp27; GPX4
资金
- Ministry of Science and Technology (MOST ) [106-2321-B-039-003, 109-2321-B-039-003, 109-2314-B-075-070-MY3, 109-2314-B-010-052-MY3, 106-2314-B-075-030-MY3]
- China Medical University [CMU110-Z-05]
- China Medical University Hospital [DMR-108-BC-5]
- Taipei Veterans General Hospital [V109C-058, V110C-109, V110C-069, V109C-015]
- Lung Cancer Foundation
Cancer stem cells (CSCs) in esophageal squamous cell carcinoma are more susceptible to ferroptosis-inducing agents, but can be rescued from cell death by activating Hsp27 to upregulate GPX4. Targeting Hsp27 or GPX4 to block this protective mechanism against ferroptosis may be a potential treatment strategy for eradicating CSCs in this type of cancer.
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.
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