Sophoridine suppresses macrophage-mediated immunosuppression through TLR4/IRF3 pathway and subsequently upregulates CD8+ T cytotoxic function against gastric cancer

Zhuang, Haiwen; Dai, Xudong; Zhang, Xiaoyu; Mao, Zhongqi; Huang, Haifang

doi:10.1016/j.biopha.2019.109636

Cited by 55 publications

(62 citation statements)

References 26 publications

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“…In a murine model of nasopharyngeal carcinoma, cancer progression is mediated by EBV encoded RNAs (EBER)-triggered inflammation dependent on the phosphorylation of p38 and IRF3 [91]. However, TAM polarization to pro-inflammatory M1 status can also dependent on TLR3-and TLR4-IRF3 signaling [28,29]. IRF3 phosphorylation and transcriptional activity is regulated by Smad2 and Smad3 [92].…”

Section: Interferon Regulatory Factorsmentioning

confidence: 99%

Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

Larionova

Kazakova

Patysheva

et al. 2020

Cancers

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Macrophages are key innate immune cells in the tumor microenvironment (TME) that regulate primary tumor growth, vascularization, metastatic spread and tumor response to various types of therapies. The present review highlights the mechanisms of macrophage programming in tumor microenvironments that act on the transcriptional, epigenetic and metabolic levels. We summarize the latest knowledge on the types of transcriptional factors and epigenetic enzymes that control the direction of macrophage functional polarization and their pro- and anti-tumor activities. We also focus on the major types of metabolic programs of macrophages (glycolysis and fatty acid oxidation), and their interaction with cancer cells and complex TME. We have discussed how the regulation of macrophage polarization on the transcriptional, epigenetic and metabolic levels can be used for the efficient therapeutic manipulation of macrophage functions in cancer.

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Section: Interferon Regulatory Factorsmentioning

confidence: 99%

Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

Larionova

Kazakova

Patysheva

et al. 2020

Cancers

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“…Consistent with this, sophoridine has been proved that can educate tumor-associated macrophages (TAMs) polarize to M1-TAMs and suppressed M2-TAMs polarization through TLR4/IRF3 axis. In addition, it can inhibit the migration ability of macrophages and reshape the immune microenvironment of gastric cancer [79]. Taken together, we propose that CKI can not only directly inhibit the proliferation and metastasis of gastric cancer tumor cells, but also improve the prognosis of cancer patients through immunotherapy.…”

Section: Discussionmentioning

confidence: 78%

A novel multi-scale bioinformatics strategy for identifying the molecular mechanism by insighting into ceRNA network integrating WGCNA and meta-analysis: compound kushen injection for treating gastric carcinoma as a proof

Zhou

Zhang

Guo

et al. 2020

Preprint

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BackgroundGastric carcinoma (GC) is a severe digestive system tumor with high morbidity and mortality and poor prognosis, of which the novel treatments are urgently needed. Compound kushen injection (CKI), a classic Chinese medicine injection, has been widely used to treat a variety of tumors in clinical for decades. In recent years, a growing number of studies have confirmed that CKI has a favorable therapeutic effect on GC, but there are few reports on the potential molecular mechanism of action.MethodsHere, using network pharmacology as the core concept, we identified the ceRNA network and key targets of CKI in the treatment of GC. In order to further explore the impact of key targets, we conducted a meta-analysis of them and compared the expression differences between GC tissues and normal tissues. Functional analysis was utilized to understand the biological regulation pathways involved in key genes. Moreover, we further detected the significance of key genes for the prognosis of GC through survival analysis and immune infiltration analysis. Finally, molecular docking simulation was adopted so as to verify the combination of CKI components and key targets.ResultsAnalysis of the ceRNA network of CKI on GC illustrated that the potential molecular mechanism of CKI was possible to regulate PI3K-AKT and Toll-like receptor signaling pathways by intervening hub genes including AKR1B1, MMP2 and PTGERR3.ConclusionsIn conclusion, this study not only partially highlighted the molecular mechanism of CKI in GC therapy but also provided a novel strategy for exploring the effective mechanisms of traditional Chinese medicine formulations.

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“…Recently, Sophoridine has been further reported with potential anti-tumor effect through regulating TAMs and CD8 + T cells in gastric cancer microenvironment [17] . However, the directly effects of Sophoridine on gastric cancer cells is remaining unclear.…”

Section: Discussionmentioning

confidence: 99%

“…In gastric cancer, one of the most common and deadly neoplasms, evidence have shown that Sophoridine reshapes gastric cancer immune microenvironment via inhibiting chemotaxis and M2 polarization of tumor-associated macrophages (TAMs), and thus leading to the increased proliferation and cytotoxic function of CD8 + T cells [17] . However, the direct effects and underlying mechanism of Sophoridine on gastric cancer cells is remaining unclear.…”

Section: Introductionmentioning

confidence: 99%

Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer

Peng

Guan

Luo

et al. 2020

Preprint

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Background: This study ought to further explore the anti-tumor effects of Sophoridine on gastric cancer cells.Methods: Cell viability assay (CCK-8 assay) was used to measure the IC50 values of Sophoridine on gastirc cancer AGS and SGC7901 cell lines and normal gastric epithelial cell line GES-1. EdU and colony formation assay were performed to confirm the cytotoxic effect of Sophoridine on AGS and SGC7901 cells. The apoptotic effects of Sophoridine on AGS and SGC7901 cells were measured by Flow cytometry. Transwell assay was used to evaluate the effects of Sophoridine on migration and invasion of AGS and SGC7901 cells. The protein expression of Sophoridine on AGS and SGC7901 cells were detected via Western blot. Results: We demonstrated that Sophoridine exerts potent tumor-suppressive activities, including inhibition of proliferation, colony formulation, migration and invasion, as well as induction of apoptosis of gastric cancer cells. In addition, we further showed that Sophoridine induces G2/M cell cycle arrest via inhibiting double-stranded DNA breaks repair and enhances the efficacy of cisplatin in gastric cancer cells. Molecular studies further revealed that Sophoridine depends on Estrogen-related receptor gamma (ESRRG) to perform tumor-suppressive activities and which leads to the degradation of β-catenin in an ubiquitin-proteasome pathway independent manner.Conclusions: Our study provided the promising preclinical anti-tumor evidence for the potential application of Sophoridine against gastric cancer.

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Sophoridine suppresses macrophage-mediated immunosuppression through TLR4/IRF3 pathway and subsequently upregulates CD8+ T cytotoxic function against gastric cancer

Cited by 55 publications

References 26 publications

Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

A novel multi-scale bioinformatics strategy for identifying the molecular mechanism by insighting into ceRNA network integrating WGCNA and meta-analysis: compound kushen injection for treating gastric carcinoma as a proof

Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer

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