Ferroptosis is a highly regulated tumor suppressor process. Loss or mutation of TP53 can cause changes in sensitivity to ferroptosis. Mutations in TP53 may be associated with the malignant or indolent progression of ground glass nodules
in early lung cancer, but whether ferroptosis may also be involved in determining
this biological process has not yet been determined. Using in vivo and in vitro gain- and loss-of-function approaches, this study used clinical tissue for mutation
analysis and pathological research to examine whether wild-type TP53 inhibits the expression of forkhead box M1 (FOXM1) by binding to peroxisome proliferator-activated
receptor-γ coactivator 1α, maintaining the mitochondrial function and thus affecting
the sensitivity to ferroptosis, whereas this function is absent in mutant cells, resulting
in overexpression of FOXM1 and ferroptosis resistance. Mechanistically, FOXM1 can
activate the transcription level of myocyte-specific enhancer factor 2C in the mitogen-activated
protein kinase signaling pathway, leading to stress protection when exposed to ferroptosis
inducers. This study provides new insights into the mechanism of association between
TP53 mutation and ferroptosis tolerance, which can aid a deeper understanding of the role
of TP53 in the malignant progression of lung cancer.
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Article info
Publication history
Published online: May 24, 2023
Accepted:
May 2,
2023
Publication stage
In Press Journal Pre-ProofFootnotes
Supported by Key Research and Development Program of Hunan Province grant 2019SK2253.
Disclosures: None declared.
Identification
Copyright
© 2023 Published by Elsevier Inc. on behalf of the American Society for Investigative Pathology.
