Cucurbitacin B inhibits non-small cell lung cancer in vivo and in vitro by triggering TLR4/NLRP3/GSDMD-dependent pyroptosis

Yuan, Renyikun; Zhao, Wentong; Wang, Qinqin; He, Jiawei; Han, Shan; Gao, Hongwei; Feng, Yulin; Yang, Shilin

doi:10.1016/j.phrs.2021.105748

Cited by 156 publications

(90 citation statements)

References 62 publications

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“…In addition, CuB has protective effect on acute lung injury and acute liver damage through inhibiting inflammatory responses [ 27 ]. In our previous study, we found that CuB at 100 nM could induce pyroptosis in A549 cells through TLR4/NLRP3/GSDMD signaling pathways, and administration with CuB at 0.25 mg/kg, 0.5 mg/kg and 0.75 mg/kg inhibited the tumor growth in NSCLC xenograft mice model [ 28 ]. However, whether CuB at safety concentration has inhibition effect on EMT was not clearly.…”

Section: Discussionmentioning

confidence: 99%

Cucurbitacin B inhibits TGF-β1-induced epithelial–mesenchymal transition (EMT) in NSCLC through regulating ROS and PI3K/Akt/mTOR pathways

et al. 2022

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Background Lung cancer is the leading cause of cancer mortality worldwide, and most of the patients after treatment with EGF-TKIs develop drug resistance, which is closely correlated with EMT. Cucurbitacin B (CuB) is a natural product of the Chinese herb Cucurbitaceae plant, which has a favorable role in anti-inflammation and anti-cancer activities. However, the effect of CuB on EMT is still far from fully explored. In this study, the inhibition effect of CuB on EMT was investigated. Methods In this study, TGF-β1 was used to induce EMT in A549 cells. MTS assay was used to detect the cell viability of CuB co-treated with TGF-β1. Wound healing assay and transwell assay were used to determine the migration and invasion capacity of cells. Flow cytometry and fluorescence microscope were used to detect the ROS level in cells. Western blotting assay and immunofluorescence assay were used to detect the proteins expression. Gefitinib was used to establish EGF-TKI resistant NSCLC cells. B16-F10 intravenous injection mice model was used to evaluate the effect of CuB on lung cancer metastasis in vivo. Caliper IVIS Lumina and HE staining were used to detect the lung cancer metastasis of mice. Results In this study, the results indicated that CuB inhibited TGF-β1-induced EMT in A549 cells through reversing the cell morphology changes of EMT, increasing the protein expression of E-cadherin, decreasing the proteins expression of N-cadherin and Vimentin, suppressing the migration and invasion ability. CuB also decreased the ROS production and p-PI3K, p-Akt and p-mTOR expression in TGF-β1-induced EMT in A549 cells. Furthermore, Gefitinib resistant A549 cells (A549-GR) were well established, which has the EMT characteristics, and CuB could inhibit the EMT in A549-GR cells through ROS and PI3K/Akt/mTOR pathways. In vivo study showed that CuB inhibited the lung cancer metastasis effectively through intratracheal administration. Conclusion CuB inhibits EMT in TGF-β1-induced A549 cells and Gefitinib resistant A549 cells through decreasing ROS production and PI3K/Akt/mTOR signaling pathway. In vivo study validated that CuB inhibits lung cancer metastasis in mice. The study may be supporting CuB as a promising therapeutic agent for NSCLC and Gefitinib resistant NSCLC.

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Section: Discussionmentioning

confidence: 99%

Cucurbitacin B inhibits TGF-β1-induced epithelial–mesenchymal transition (EMT) in NSCLC through regulating ROS and PI3K/Akt/mTOR pathways

et al. 2022

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“…Recent studies have identified pyroptosis as a new form of programmed cell death, which plays an essential role in tumor development and treatment mechanisms [ 8 ]. Pyroptosis has been found to play a crucial role in various cancers, such as non-small-cell lung cancer and head and neck cancer [ 34 , 35 ]. Currently, the pyroptosis-related prognostic signature has been constructed in ovarian cancer and gastric cancer, with an excellent prognostic potential [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

Signature Construction and Molecular Subtype Identification Based on Pyroptosis-Related Genes for Better Prediction of Prognosis in Hepatocellular Carcinoma

Chen

Tao

Lang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, there is a lack of adequate means of treatment prognostication for HCC. Pyroptosis is a newly discovered way of programmed cell death. However, the prognostic role of pyroptosis in HCC has not been thoroughly investigated. Here, we generated a novel prognostic signature to evaluate the prognostic value of pyroptosis-related genes (PRGs) using the data from The Cancer Genome Atlas (TCGA) database. The accuracy of the signature was validated using survival analysis through the International Cancer Genome Consortium cohort ( n = 231 ) and the First Affiliated Hospital of Wenzhou Medical University cohort ( n = 180 ). Compared with other clinical factors, the risk score of the signature was found to be associated with better patient outcomes. The enrichment analysis identified multiple pathways related with pyroptosis in HCC. Furthermore, drug sensitivity testing identified six potential chemotherapeutic agents to provide possible treatment avenues. Interestingly, patients with low risk were confirmed to be associated with lower tumor mutation burden (TMB). However, patients at high risk were found to have a higher count of immune cells. Consensus clustering was performed to identify two main molecular subtypes (named clusters A and B) based on the signature. It was found that compared with cluster B, better survival outcomes and lower TMB were observed in cluster A. In conclusion, signature construction and molecular subtype identification of PRGs could be used to predict the prognosis of HCC, which may provide a specific reference for the development of novel biomarkers for HCC treatment.

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“…Further analysis demonstrated that IL27 was indeed correlated with pyroptosis, autophagy, and apoptosis. Pyproptosis is reported to inhibit the progression of lung cancer, and breast cancer ( 47 – 49 ). Here, we showed the association of IL27 with pyroptosis, providing evidence of the mechanism underlying IL27 function in cancer.…”

Section: Discussionmentioning

confidence: 99%

Integrative Characterization of the Role of IL27 In Melanoma Using Bioinformatics Analysis

et al. 2021

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BackgroundIL27 has been reported to play dual roles in cancer; however, its effects on the tumor microenvironment (TME), immunotherapy, and prognosis in melanoma remain largely unclear. This study was aimed to uncover the effects of IL27 on TME, immunotherapy and prognosis in patients with melanoma.MethodsRNA-seq data, drug sensitivity data, and clinical data were obtained from TCGA, GEO, CCLE, and CTRP. Log-rank test was used to determine the survival value of IL27. Univariate and multivariate Cox regression analyses were employed to determine the independent predictors of survival outcomes. DAVID and GSEA were used to perform gene set functional annotations. ssGSEA was used to explore the association between IL27 and immune infiltrates. ConsensusClusterPlus was used to classify melanoma tissues into hot tumors or cold tumors.ResultsClinically, IL27 was negatively correlated with Breslow depth (P = 0.00042) and positively associated with response to radiotherapy (P = 0.038). High IL27 expression showed an improved survival outcome (P = 0.00016), and could serve as an independent predictor of survival outcomes (hazard ratio: 0.32 - 0.88, P = 0.015). Functionally, elevated IL27 expression could induce an enhanced immune response and pyroptosis (R = 0.64, P = 1.2e-55), autophagy (R = 0.37, P = 7.1e-17) and apoptosis (R = 0.47, P = 1.1e-27) in patients with melanoma. Mechanistically, elevated IL27 expression was positively correlated with cytotoxic cytokines (including INFG and GZMB), enhanced immune infiltrates, and elevated CD8/Treg ratio (R = 0.14, P = 0.02), possibly driving CD8+ T cell infiltration by suppressing β-catenin signaling in the TME. Furthermore, IL27 was significantly associated with hot tumor state, multiple predictors of response to immunotherapy, and improved drug response in patients with melanoma.ConclusionsIL27 was correlated with enriched CD8+ T cells, desirable therapeutic response and improved prognosis. It thus can be utilized as a promising modulator in the development of cytokine-based immunotherapy for melanoma.

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Cucurbitacin B inhibits non-small cell lung cancer in vivo and in vitro by triggering TLR4/NLRP3/GSDMD-dependent pyroptosis

Cited by 156 publications

References 62 publications

Cucurbitacin B inhibits TGF-β1-induced epithelial–mesenchymal transition (EMT) in NSCLC through regulating ROS and PI3K/Akt/mTOR pathways

Cucurbitacin B inhibits TGF-β1-induced epithelial–mesenchymal transition (EMT) in NSCLC through regulating ROS and PI3K/Akt/mTOR pathways

Signature Construction and Molecular Subtype Identification Based on Pyroptosis-Related Genes for Better Prediction of Prognosis in Hepatocellular Carcinoma

Integrative Characterization of the Role of IL27 In Melanoma Using Bioinformatics Analysis

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