Open AccessFerroptosis inducer erastin sensitizes NSCLC cells to celastrol through activation of the ROS–mitochondrial fission–mitophagy axis
Author(s) -
Liu Ming,
Fan Yumei,
Li Danyu,
Han Bihui,
Meng Yanxiu,
Chen Fei,
Liu Tianchan,
Song Zhiyuan,
Han Yu,
Huang Liying,
Chang Yanzhong,
Cao Pengxiu,
Nakai Akira,
Tan Ke
Publication year - 2021
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12936
Subject(s) - celastrol , mitophagy , programmed cell death , autophagy , cancer research , necroptosis , apoptosis , gene knockdown , chemistry , pharmacology , biology , biochemistry
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.