NLRP3 inflammasome activation plays a carcinogenic role through effector cytokine IL-18 in lymphoma

Zhao, Xia; Zhang, Chen; Hua, Mingqiang; Wang, Ruiqing; Zhong, Chaoqin; Yu, Jie; Han, Fengjiao; He, Na; Liu, Guoqiang; Zheng, Ni; Ji, Chunyan; Ma, Daoxin

doi:10.18632/oncotarget.21010

Cited by 48 publications

(51 citation statements)

References 42 publications

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“…The nucleotide-binding oligomerization domain-like receptors (NOD-like receptors) family pyrin domain, containing 3 (NLRP3), is the most widely studied inflammasome. A previous study demonstrated that activated NLRP3 increases IL-18 in patients with lymphoma [ 55 ]. NLRP3 inflammasome could represent a novel potential target for the treatment of breast cancer [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

NLRP3 as Putative Marker of Ipilimumab-Induced Cardiotoxicity in the Presence of Hyperglycemia in Estrogen-Responsive and Triple-Negative Breast Cancer Cells

Quagliariello

Laurentiis

Cocco

et al. 2020

IJMS

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Hyperglycemia, obesity and metabolic syndrome are negative prognostic factors in breast cancer patients. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, achieving unprecedented efficacy in multiple malignancies. However, ICIs are associated with immune-related adverse events involving cardiotoxicity. We aimed to study if hyperglycemia could affect ipilimumab-induced anticancer efficacy and enhance its cardiotoxicity. Human cardiomyocytes and estrogen-responsive and triple-negative breast cancer cells (MCF-7 and MDA-MB-231 cell lines) were exposed to ipilimumab under high glucose (25 mM); low glucose (5.5 mM); high glucose and co-administration of SGLT-2 inhibitor (empagliflozin); shifting from high glucose to low glucose. Study of cell viability and the expression of new putative biomarkers of cardiotoxicity and resistance to ICIs (NLRP3, MyD88, cytokines) were quantified through ELISA (Cayman Chemical) methods. Hyperglycemia during treatment with ipilimumab increased cardiotoxicity and reduced mortality of breast cancer cells in a manner that is sensitive to NLRP3. Notably, treatment with ipilimumab and empagliflozin under high glucose or shifting from high glucose to low glucose reduced significantly the magnitude of the effects, increasing responsiveness to ipilimumab and reducing cardiotoxicity. To our knowledge, this is the first evidence that hyperglycemia exacerbates ipilimumab-induced cardiotoxicity and decreases its anticancer efficacy in MCF-7 and MDA-MB-231 cells. This study sets the stage for further tests on other breast cancer cell lines and primary cardiomyocytes and for preclinical trials in mice aimed to decrease glucose through nutritional interventions or administration of gliflozines during treatment with ipilimumab.

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Section: Discussionmentioning

confidence: 99%

NLRP3 as Putative Marker of Ipilimumab-Induced Cardiotoxicity in the Presence of Hyperglycemia in Estrogen-Responsive and Triple-Negative Breast Cancer Cells

Quagliariello

Laurentiis

Cocco

et al. 2020

IJMS

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“…Furthermore, studies have highlighted the role of individual inflammasome sensors in tumor proliferation and survival. NLRP3 activation in lymphoma cells produce IL-18 which attenuates dexamethasone-induced apoptosis 38 thereby promoting their survival (FIG. 2a).…”

Section: Inflammasome Activationmentioning

confidence: 99%

Diverging inflammasome signals in tumorigenesis and potential targeting

2019

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Inflammasomes are molecular platforms that assemble upon sensing various intracellular stimuli. Inflammasome assembly leads to activation of caspase-1, thereby promoting the secretion of bioactive interleukin-1β and interleukin-18 and inducing an inflammatory cell death called pyroptosis. Effectors of the inflammasome efficiently drive an immune response, primarily providing protection against microbial infections and mediating control over sterile insults. However, aberrant inflammasome signaling is associated with pathogenesis of inflammatory and metabolic diseases, neurodegeneration, and malignancies. Chronic inflammation perpetuated by inflammasome activation plays a central role in all stages of tumorigenesis, including immunosuppression, proliferation, angiogenesis, and metastasis. Conversely, inflammasome signaling also contributes to tumor suppression by maintaining intestinal barrier integrity, which portrays the diverse roles of inflammasomes in tumorigenesis. Studies have underscored the significance of environmental factors, such as diet and gut microbiota [G] in inflammasome signaling, which in turn influences tumorigenesis. In this review, we deliver an overview of the interplay between inflammasomes and tumorigenesis and discuss their potential as a therapeutic target. ToC blurb Inflammasome signaling in myeloid cells largely protects against microbial infections. Aberrant inflammasome signaling promotes chronic inflammation, which contributes to tumorigenesis. This Review presents an overview of the diverging roles of inflammasomes in cancer and discuss its targeting potential in anti-cancer therapy.

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“…NACHT, LRR and PYD domains-containing protein 3 (NLRP3) is the most widely studied inflammasome. A previous study demonstrated that activated NLRP3 significantly promoted the protein expression level of IL-18 in the plasma of patients with lymphoma (6). Furthermore, it was identified that the activation of caspase-1 may trigger the maturation and secretion of IL-18 (7).…”

Section: Introductionmentioning

confidence: 97%

NLRP3 inflammasome inactivation driven by miR‑223‑3p reduces tumor growth and increases anticancer immunity in breast cancer

Zhang

Zang

et al. 2019

Mol Med Report

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MicroRNA-233-3p (miR-223-3p) is considered an important cancer-associated marker. The NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome represents a novel potential target for the treatment of breast cancer. Therefore, it was hypothesized that miR-223-3p may affect tumor growth and immunosuppression in breast cancer by inhibiting the NLRP3 inflammasome. In the present study, an increased expression level of NLRP3 was detected in three breast cancer cell lines compared with normal mammary epithelial cells (HMEC). Suppressing the expression of NLRP3 in MCF-7 cell lines increased the apoptotic rate of breast cancer cells and reduced the proliferative capacity. NLRP3 was identified to be a direct target of miR-233-3p using a luciferase assay. In addition, miR-233-3p mimics inhibited the NLRP3-dependent processes in cancer cells by suppressing the NLRP3 expression level and the protein expression levels of its downstream factors, including PYD and CARD domain containing protein, interleukin-1β and interleukin-18. In vivo experiments demonstrated the suppressive effect of miR-233-3p in tumor growth and immunosuppression. Collectively these findings suggested that the inactivation of the NLRP3 inflammasome driven by miR-223-3p reduced the growth and immunosuppression of breast cancer in vitro and in vivo , and may represent a novel therapeutic strategy in treating breast cancer.

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NLRP3 inflammasome activation plays a carcinogenic role through effector cytokine IL-18 in lymphoma

Cited by 48 publications

References 42 publications

NLRP3 as Putative Marker of Ipilimumab-Induced Cardiotoxicity in the Presence of Hyperglycemia in Estrogen-Responsive and Triple-Negative Breast Cancer Cells

NLRP3 as Putative Marker of Ipilimumab-Induced Cardiotoxicity in the Presence of Hyperglycemia in Estrogen-Responsive and Triple-Negative Breast Cancer Cells

Diverging inflammasome signals in tumorigenesis and potential targeting

NLRP3 inflammasome inactivation driven by miR‑223‑3p reduces tumor growth and increases anticancer immunity in breast cancer

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