Maxim (TTM), a traditional Chinese medicine, has been demonstrated to have a potent anti-tumor effect. Recently, polyphyllin VI (PPVI), a main saponin isolated from TTM, was reported by us to significantly suppress the proliferation of non-small cell lung cancer (NSCLC) via the induction of apoptosis and autophagy in vitro and in vivo. In this study, we further found that the NLRP3 inflammasome was activated in PPVI administrated A549-bearing athymic nude mice. As is known to us, pyroptosis is an inflammatory form of caspase-1-dependent programmed cell death that plays an important role in cancer. By using A549 and H1299 cells, the in vitro effect and action mechanism by which PPVI induces activation of the NLRP3 inflammasome in NSCLC were investigated. The anti-proliferative effect of PPVI in A549 and H1299 cells was firstly measured and validated by MTT assay. The activation of the NLRP3 inflammasome was detected by using Hoechst33324/PI staining, flow cytometry analysis and real-time live cell imaging methods. We found that PPVI significantly increased the percentage of cells with PI signal in A549 and H1299, and the dynamic change in cell morphology and the process of cell death of A549 cells indicated that PPVI induced an apoptosis-to-pyroptosis switch, and, ultimately, lytic cell death. In addition, belnacasan (VX-765), an inhibitor of caspase-1, could remarkably decrease the pyroptotic cell death of PPVI-treated A549 and H1299 cells. Moreover, by detecting the expression of NLRP3, ASC, caspase-1, IL-1β, IL-18 and GSDMD in A549 and h1299 cells using Western blotting, immunofluorescence imaging and flow cytometric analysis, measuring the caspase-1 activity using colorimetric assay, and quantifying the cytokines level of IL-1β and IL-18 using ELISA, the NLRP3 inflammasome was found to be activated in a dose manner, while VX-765 and necrosulfonamide (NSA), an inhibitor of GSDMD, could inhibit PPVI-induced activation of the NLRP3 inflammasome. Furthermore, the mechanism study found that PPVI could activate the NF-κB signaling pathway via increasing reactive oxygen species (ROS) levels in A549 and H1299 cells, and -acetyl-L-cysteine (NAC), a scavenger of ROS, remarkably inhibited the cell death, and the activation of NF-κB and the NLRP3 inflammasome in PPVI-treated A549 and H1299 cells. Taken together, these data suggested that PPVI-induced, caspase-1-mediated pyroptosis via the induction of the ROS/NF-κB/NLRP3/GSDMD signal axis in NSCLC, which further clarified the mechanism of PPVI in the inhibition of NSCLC, and thereby provided a possibility for PPVI to serve as a novel therapeutic agent for NSCLC in the future.
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http://dx.doi.org/10.3390/cancers12010193 | DOI Listing |
ACS Chem Biol
December 2024
Department of Urology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
MicroRNAs (miRNAs) play a significant role in tumor progression, and regulating miRNA expression with small molecules may offer a new approach to cancer therapy. Among them, miRNA-20b has been found to be dysregulated in several cancers, including nonsmall cell lung cancer (NSCLC). Herein, an in silico high-throughput computer screen was conducted to identify small molecules that downregulate miR-20b using the three-dimensional structure of the Dicer binding site on pre-miR-20b.
View Article and Find Full Text PDFBiochim Biophys Acta Mol Basis Dis
December 2024
Department of General Practice, The Third Xiangya Hospital of Central South University, 138 Tongzipo Road, Yuelu District, Changsha 410013, Hunan, China. Electronic address:
The level of serum bilirubin is associated with the incidence of lung cancer in both smokers and non-smokers, but the specific mechanism is unknown. Bilirubin nanoparticles (BRNPs) were synthesized to explore the effects on Treg/Th17 immunity and gut microbiota in Lewis Lung Carcinoma (LLC) mice, to provide insights for the treatment of lung adenocarcinoma. 10 μg/mL BRNPs promoted apoptosis of A549, NCI-H1299 and LLC cells.
View Article and Find Full Text PDFBiochem Biophys Res Commun
January 2025
Institute of Cytology, Russian Academy of Sciences, 194064, St. Petersburg, Russia. Electronic address:
Although an E3 ligase MDM2 is the major negative regulator of the p53 tumor suppressor, a growing body of evidence suggests its p53-independent oncogenic properties. In particular, MDM2 has been shown to regulate serine metabolism independently of p53 status in several types of neoplasia, including NSCLC. Using the GSEA approach and publicly available molecular data on NSCLC tumors, our bioinformatics data suggest that MDM2 affects a number of metabolic genes, particularly those encoding components of the electron transport chain (ETC).
View Article and Find Full Text PDFZhonghua Zhong Liu Za Zhi
December 2024
Department of Respiratory and Critical Care Medicine, the Affiliated People's Hospital of Ningbo University, Ningbo315000, China.
To study the effects and mechanisms of activation of human lung fibroblasts (MRC-5) by exosomal RNA hsa _ circ _ 0006357 (circEZH2) derived from non-small cell lung cancer. Western blot was used to detect exosome molecular markers, reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) and cell invasion assays to detect the effect of non-small cell lung cancer-derived exosomes on MRC-5 activation. A circRNA microarray analysis was performed in serum exosomes from patients with non-small cell lung cancer (collected at Ningbo University People's Hospital, September 2023), and levels of circEZH2 were measured in serum exosomes from non-small cell lung cancer by RT-qPCR analysis.
View Article and Find Full Text PDFInt Immunopharmacol
January 2025
Department of Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital Affiliated to Shandong First Medical University, Shandong Academy of Medical Science, Jinan, Shandong, China; Department of Radiation Oncology, Shandong University Cancer Center, Jinan, Shandong, China. Electronic address:
Background: The role of cancer-associated fibroblasts (CAFs) in modulating the anti-tumor immune response in lung adenocarcinoma (LUAD) remains elusive, primarily due to the heterogeneous nature of these cells. This heterogeneity muddles the understanding of their impact on immunotherapy effectiveness.
Methods: We utilized the LUAD single-cell dataset to precisely classify tumor cells and CAFs.
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