Ferroptosis inducer erastin sensitizes NSCLC cells to celastrol through activation of the ROS-mitochondrial fission-mitophagy axis.
Animals
Carcinoma, Non-Small-Cell Lung
/ metabolism
Cell Line, Tumor
Female
Ferroptosis
/ drug effects
Humans
Lung Neoplasms
/ metabolism
Mice
Mice, Inbred BALB C
Mitochondrial Dynamics
/ drug effects
Mitophagy
/ drug effects
Pentacyclic Triterpenes
/ pharmacology
Piperazines
/ pharmacology
Reactive Oxygen Species
/ metabolism
Xenograft Model Antitumor Assays
autophagy
celastrol
erastin
mitochondrial fission
mitophagy
non-small-cell lung cancer
Journal
Molecular oncology
ISSN: 1878-0261
Titre abrégé: Mol Oncol
Pays: United States
ID NLM: 101308230
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
revised:
06
02
2021
received:
27
08
2020
accepted:
16
02
2021
pubmed:
7
3
2021
medline:
29
3
2022
entrez:
6
3
2021
Statut:
ppublish
Résumé
Despite recent progress in non-small-cell lung cancer (NSCLC) treatment, treatment outcomes remain poor, mainly because of treatment resistance or toxicity. Erastin is a ferroptosis inducer that has shown promising cytotoxic effects in various types of cancers, including NSCLC. Celastrol is a triterpene extracted from the Tripterygium wilfordii that exhibits potential anticancer activity. However, the side effects of celastrol are severe and limit its clinical application. Combination therapy is a promising strategy to overcome the compensatory mechanisms and unwanted off-target effects. In the present study, we found that erastin synergized with celastrol to induce cell death at nontoxic concentrations. The combined treatment with celastrol and erastin significantly increased reactive oxygen species (ROS) generation, disrupted mitochondrial membrane potential, and promoted mitochondrial fission. Furthermore, cotreatment with erastin and celastrol initiated ATG5/ATG7-dependent autophagy, PINK1/Parkin-dependent mitophagy, and the expression of heat shock proteins (HSPs) in an HSF1-dependent manner. HSF1 knockdown further enhanced cell death in vitro and inhibited tumor growth in vivo. Our findings indicate that the combination of celastrol with erastin may represent a novel therapeutic regimen for patients with NSCLC and warrants further clinical evaluation.
Identifiants
pubmed: 33675143
doi: 10.1002/1878-0261.12936
pmc: PMC8334255
doi:
Substances chimiques
Pentacyclic Triterpenes
0
Piperazines
0
Reactive Oxygen Species
0
erastin
0
celastrol
L8GG98663L
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2084-2105Informations de copyright
© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
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