Dihydroartemisinin‐driven TOM70 inhibition leads to mitochondrial destabilization to induce pyroptosis against lung cancer

Enhancement of malignant cell immunogenicity to relieve immunosuppression of lung cancer microenvironment is essential in lung cancer treatment. In previous study, we have demonstrated that dihydroartemisinin (DHA), a kind of phytopharmaceutical, is effective in inhibiting lung cancer cells and boos...

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Published in:Phytotherapy research 2024-08, Vol.38 (8), p.3856-3876
Main Authors: Li, Liu‐Gen, Hu, Jun, Han, Ning, Chen, Nan‐Nan, Yu, Ting‐Ting, Ren, Tao, Xu, Hua‐Zhen, Peng, Xing‐Chun, Li, Xian‐Yu, Ma, Tian‐Qi, Chen, Hao, Zhang, Lei, Chen, Xiao, Wang, Mei‐Fang, Li, Tong‐Fei
Format: Article
Language:English
Subjects:
Cancer therapies
cGAS/STING/NLRP3
Cytoplasm
Destabilization
Dihydroartemisinin
Effectiveness
Flow cytometry
Homeostasis
Immunogenicity
Immunosuppression
In vivo methods and tests
Lung cancer
Microenvironments
Mitochondria
Mitochondrial DNA
mitochondrial homeostasis
mtDNA
Pronase
Pyroptosis
Signal transduction
Thermal stability
Thermophoresis
TOM70
Translocation
Western blotting
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Summary:Enhancement of malignant cell immunogenicity to relieve immunosuppression of lung cancer microenvironment is essential in lung cancer treatment. In previous study, we have demonstrated that dihydroartemisinin (DHA), a kind of phytopharmaceutical, is effective in inhibiting lung cancer cells and boosting their immunogenicity, while the initial target of DHA's intracellular action is poorly understood. The present in‐depth analysis aims to reveal the influence of DHA on the highly expressed TOM70 in the mitochondrial membrane of lung cancer. The affinity of DHA and TOM70 was analyzed by microscale thermophoresis (MST), pronase stability, and thermal stability. The functions and underlying mechanism were investigated using western blots, qRT‐PCR, flow cytometry, and rescue experiments. TOM70 inhibition resulted in mtDNA damage and translocation to the cytoplasm from mitochondria due to the disruption of mitochondrial homeostasis. Further ex and in vivo findings also showed that the cGAS/STING/NLRP3 signaling pathway was activated by mtDNA and thereby malignant cells underwent pyroptosis, leading to enhanced immunogenicity of lung cancer cells in the presence of DHA. Nevertheless, DHA‐induced mtDNA translocation and cGAS/STING/NLRP3 mobilization were synchronously attenuated when TOM70 was replenished. Finally, DHA was demonstrated to possess potent anti‐lung cancer efficacy in vitro and in vivo. Taken together, these data confirm that TOM70 is an important target for DHA to disturb mitochondria homeostasis, which further activates STING and arouses pyroptosis to strengthen immunogenicity against lung cancer thereupon. The present study provides vital clues for phytomedicine‐mediated anti‐tumor therapy.
ISSN:0951-418X
1099-1573
1099-1573
DOI:10.1002/ptr.8242