The effects of NLRP3 inflammasome inhibition by MCC950 on LPS-induced pancreatic adenocarcinoma inflammation

Yaw, Alan Cheuk Keong; Chan, Elaine Wan Ling; Yap, Jeremy Kean Yi; Wu, Chun

doi:10.1007/s00432-020-03274-y

Cited by 30 publications

(19 citation statements)

References 42 publications

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“… 298 , 304 , 305 MCC950 is a specific NLRP3 antagonist, which can prevent its activation or maintain its activation state. 468 β-Carotene has been shown to directly bind to the PYD of NLRP3, thereby blocking the association between NLRP3 and its adaptor protein and ultimately inhibiting the activation of NLRP3 inflammasomes. 469 This result further complements the new pharmacological strategy to prevent NLRP3 inflammasome-driven gouty arthritis.…”

Section: Clinical Therapy Of Prrsmentioning

confidence: 99%

Pattern recognition receptors in health and diseases

2021

Sig Transduct Target Ther

726

515

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Pattern recognition receptors (PRRs) are a class of receptors that can directly recognize the specific molecular structures on the surface of pathogens, apoptotic host cells, and damaged senescent cells. PRRs bridge nonspecific immunity and specific immunity. Through the recognition and binding of ligands, PRRs can produce nonspecific anti-infection, antitumor, and other immunoprotective effects. Most PRRs in the innate immune system of vertebrates can be classified into the following five types based on protein domain homology: Toll-like receptors (TLRs), nucleotide oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), C-type lectin receptors (CLRs), and absent in melanoma-2 (AIM2)-like receptors (ALRs). PRRs are basically composed of ligand recognition domains, intermediate domains, and effector domains. PRRs recognize and bind their respective ligands and recruit adaptor molecules with the same structure through their effector domains, initiating downstream signaling pathways to exert effects. In recent years, the increased researches on the recognition and binding of PRRs and their ligands have greatly promoted the understanding of different PRRs signaling pathways and provided ideas for the treatment of immune-related diseases and even tumors. This review describes in detail the history, the structural characteristics, ligand recognition mechanism, the signaling pathway, the related disease, new drugs in clinical trials and clinical therapy of different types of PRRs, and discusses the significance of the research on pattern recognition mechanism for the treatment of PRR-related diseases.

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Section: Clinical Therapy Of Prrsmentioning

confidence: 99%

Pattern recognition receptors in health and diseases

2021

Sig Transduct Target Ther

726

515

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“…Recently, researchers also focused on contributing chronic inflammation created by NLRP3 activation to carcinogenesis, including proliferation, angiogenesis, immunosuppression, and metastasis Liu et al (2021) , Huang et al (2017) , and Chen et al (2018) showed that blockage of the NLRP3 inflammasome could enhance the antitumor immune responses in head and neck squamous cell carcinoma, suggesting that the NLRP3 inflammasome pathway may be regarded as a novel approach for the treatment of head and neck squamous cell carcinoma. Inhibition of the NLRP3 inflammasome through an NLRP3-specific antagonist could also reduce the cell viability in pancreatic adenocarcinoma ( Yaw et al, 2020 ). Moreover, knockdown of NLRP3 was found to diminish the migration and invasion abilities of colorectal carcinoma cells ( Wang et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

NLRP3 Overexpression Associated With Poor Prognosis and Presented as an Effective Therapeutic Target in Osteosarcoma

et al. 2021

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Despite the development of diagnostic and treatment strategies, the survival outcome of patients with osteosarcoma remains poor. Nod-like receptor protein 3 (NLRP3) plays a crucial role in the inflammasome pathway, which is related to the progression of various tumors. However, the effect of NLRP3 on osteosarcoma has not yet been well explored. Our study aimed to investigate the role of NLRP3 in the malignant biological behavior of osteosarcoma as well as its therapeutic value. Immunohistochemistry was applied to investigate the NLRP3 expression in osteosarcoma and osteochondroma specimens. Cell Counting Kit-8, colony formation, wound healing, transwell, and flow cytometry assays were used to explore the contribution of NLRP3 to the proliferation, migration, invasion, apoptosis and cell cycle distribution of osteosarcoma cells in vitro. Western blot was performed to evaluate the expression of NLRP3 and the related proteins in osteosarcoma cell lines after the blockade of NLRP3 using CY-09 and lentivirus intervention. Furthermore, tumor formation assay was used to analyze the effect of NLRP3 on the growth of osteosarcoma in vivo. The results showed that the NLRP3 protein was overexpressed in osteosarcoma, which was independently correlated with the poor prognosis of patients. Moreover, NLRP3 suppression by the inhibitor of CY-09 or lentivirus-induced gene knockdown inhibited the cell proliferation, migration, invasion and promoted the cell apoptosis and G1 cell cycle arrest in osteosarcoma via targeting the inflammasome pathway. Our in vivo results confirmed that the inhibition of NLRP3 suppressed the tumor formation of osteosarcoma. In conclusion, NLRP3 may be regarded as an independent prognostic biomarker and a potential therapeutic target for osteosarcoma.

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“…Excitingly, we found a recent report that more completely elaborates the role of NLRP3, CASP1, and IL- β in pancreatic cancer. According to a previous study, LPS-induced inflammation in the presence of ATP activates NLRP3, which enhances pancreatic cancer cell proliferation by boosting caspase-1 activity, resulting in total IL-1 β production [ 46 ]. Although the term “pyroptosis” is not explicitly stated in the article, we believe that the mechanism detailed in the study is most likely the canonical CASP1-dependent pyroptosis pathway.…”

Section: Discussionmentioning

confidence: 99%

Development of a Prognostic Model Based on Pyroptosis-Related Genes in Pancreatic Adenocarcinoma

Peng

2022

Disease Markers

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Background. The importance of pyroptosis in tumorigenesis and cancer progression is becoming increasingly apparent. However, the efficacy of using pyroptosis-related genes (PRGs) in predicting the prognosis of pancreatic adenocarcinoma (PAAD) patients is unknown. Methods. This investigation used two databases to obtain expression data for PAAD patients. Differentially expressed PRGs (DEPRGs) were identified between PAAD and control samples. Several bioinformatic approaches were used to analyze the biological functions of DEPRGs and to identify prognostic DERPGs. A miRNA-prognostic DEPRG-transcription factor (TF) regulatory network was created via the miRNet online tool. A risk score model was created after each patient’s risk score was calculated. The microenvironments of the low- and high-risk groups were assessed using xCell, the expression of immune checkpoints was determined, and gene set variation analysis (GSVA) was performed. Finally, the efficacy of certain potential drugs was predicted using the pRRophetic algorithm, and the results in the high- and low-risk groups were compared. Results. A total of 13 DEPRGs were identified between PAAD and control samples. Functional enrichment analysis showed that the DEPRGs had a close relationship with inflammation. In univariate and multivariate Cox regression analyses, GSDMC, IRF1, and PLCG1 were identified as prognostic biomarkers in PAAD. The results of the miRNA-prognostic DEPRG-TF regulatory network showed that GSDMC, IRF1, and PLCG1 were regulated by both specific and common miRNAs and TFs. Based on the risk score and other independent prognostic indicators, a nomogram with a good ability to predict the survival of PAAD patients was developed. By evaluating the tumor microenvironment, we observed that the immune and metabolic microenvironments of the two groups were substantially different. In addition, individuals in the low-risk group were more susceptible to axitinib and camptothecin, whereas lapatinib might be preferred for patients in the high-risk group. Conclusion. Our study revealed the prognostic value of PRGs in PAAD and created a reliable model for predicting the prognosis of PAAD patients. Our findings will benefit the prognostication and treatment of PAAD patients.

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The effects of NLRP3 inflammasome inhibition by MCC950 on LPS-induced pancreatic adenocarcinoma inflammation

Cited by 30 publications

References 42 publications

Pattern recognition receptors in health and diseases

Pattern recognition receptors in health and diseases

NLRP3 Overexpression Associated With Poor Prognosis and Presented as an Effective Therapeutic Target in Osteosarcoma

Development of a Prognostic Model Based on Pyroptosis-Related Genes in Pancreatic Adenocarcinoma

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