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Evaluation of Caspase Activation to Assess Innate Immune Cell Death
Published on: January 20, 2023
Platycodon D promotes immunogenic cell death in lung cancer cells by targeting NFS1 to induce PANoptosis
Mingjie Wu1, Jia Wang2, Yunjie Wu2
1School of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Background:
Lung cancer remains one of the most lethal malignancies worldwide, with therapeutic resistance and low response rates representing major clinical challenges. The biosynthetic enzyme NFS1 has been implicated in tumour progression across various cancer types. PANoptosis is a recently identified type of cell death that can increase antitumour immunity, resulting in effective tumour suppression. Platycodin D (PD), a triterpenoid saponin isolated from the traditional Chinese medicine Platycodon grandiflorus, has demonstrated anticancer effects through mechanisms such as apoptosis induction and autophagy regulation.
Purpose:
This study aimed to investigate the mechanism by which PD targets NFS1 to induce PANoptosis and increase antitumour immunity in lung cancer.
Methods:
The antiproliferative effect of PD was assessed using a CCK-8 assay. Changes in the expression of key PANoptosis-related proteins were analysed by Western blotting, and YP1/PI et al. were used to visualize different modes of cell death. CETSAs and DARTSs were performed to validate the direct interaction between PD and NFS1. ELISA and flow cytometry were used to measure the release of ICD-related molecules and DCs maturation, respectively. Mouse models were established to evaluate the in vivo antitumour efficacy and immunomodulatory effects of PD, both alone and in combination with NFS1 siRNA.
Results:
PD inhibited lung cancer cell proliferation in a dose-dependent manner. Mechanistically, PD directly bound to NFS1, downregulated its expression, and induced significant accumulation of ROS, leading to the activation of PANoptosis. Furthermore, PD treatment triggered the release of ATP and HMGB1, and promoted DCs maturation. In vivo studies confirmed that PD significantly suppressed tumour growth and acted synergistically with NFS1 knockdown to promote antitumour immunity.
Conclusion:
Our findings demonstrate that PD targets NFS1 to trigger ROS-dependent PANoptosis and activate antitumour immune responses, providing a novel immunotherapy sensitization strategy for lung cancer patients.
Insights
Platycodin D (PD) targets the NFS1 enzyme to induce programmed cell death (PANoptosis) in lung cancer cells. This process enhances antitumour immunity, offering a new strategy for cancer immunotherapy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Lung cancer presents significant therapeutic challenges due to resistance and low response rates.
- The enzyme NFS1 is implicated in tumor progression, while PANoptosis, a form of cell death, can enhance anti-tumor immunity.
- Platycodin D (PD), derived from Platycodon grandiflorus, exhibits anti-cancer properties.
Purpose of the Study:
- To investigate how Platycodin D (PD) targets NFS1 to induce PANoptosis in lung cancer.
- To determine if PD enhances anti-tumor immunity through this mechanism.
Main Methods:
- Assessed PD's antiproliferative effects using CCK-8 assays.
- Analyzed PANoptosis-related proteins via Western blotting and visualized cell death modes.
- Validated PD-NFS1 interaction using CETSAs and DARTSs; measured immune responses with ELISA and flow cytometry.
- Evaluated in vivo efficacy in mouse models, alone and with NFS1 siRNA.
Main Results:
- PD inhibited lung cancer cell proliferation dose-dependently and directly bound to NFS1, downregulating its expression.
- PD induced ROS accumulation, activating PANoptosis and triggering the release of ATP and HMGB1.
- PD promoted dendritic cell (DC) maturation and synergized with NFS1 knockdown to suppress tumor growth and boost anti-tumor immunity in vivo.
Conclusions:
- PD targets NFS1 to induce ROS-dependent PANoptosis, activating anti-tumor immune responses in lung cancer.
- This provides a novel strategy for sensitizing lung cancer patients to immunotherapy.
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