Inflammasomes in Inflammation-Induced Cancer

Lin, Chu; Zhang, Jun

doi:10.3389/fimmu.2017.00271

Cited by 79 publications

(66 citation statements)

References 235 publications

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“…NLRP1 (NALP1) is the component of the first identified inflammasome [28]. It is a pattern recognition receptor activated by various bacterial toxins including Bacillus anthracis lethal toxin [29]. For our analysis of gene expression, we also selected PKR kinase (coded by the EIF2AK2 gene), because it has antiviral effector functions and can participate in the activation of p53 by phosphorylating Ser392 [30].…”

Section: Treatment With a + N Or Cpt Upregulates Proteins Associated mentioning

confidence: 99%

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

Krześniak

Zajkowicz

Gdowicz-Kłosok

et al. 2020

Cellular Signalling

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A B S T R A C TActinomycin D and nutlin-3a (A + N) activate p53, partly through induction of phosphorylation on Ser392. The death of A549 cells induced by A + N morphologically resembles inflammation-inducing pyroptosis -cell destruction triggered by activated caspase-1. The treatment with A + N (or camptothecin) strongly upregulated caspase-1 and its two activators: IFI16 and NLRP1, however, caspase-1 activation was not detected. A549 cells may have been primed for pyroptosis, with the absence of a crucial trigger. The investigation of additional innate immunity elements revealed that A + N (or camptothecin) stimulated the expression of NLRX1, STING (stimulator of interferon genes) and two antiviral proteins, IFIT1 and IFIT3. IFI16 and caspase-1 are coded by p53regulated genes which led us to investigate regulation of NLRP1, NLRX1, STING, IFIT1 and IFIT3 in p53-dependent mode. The upregulation of NLRP1, NLRX1 and STING was attenuated in p53 knockdown cells. The upsurge of the examined genes, and activation of p53, was inhibited by C16, an inhibitor of PKR kinase. PKR was tested due to its ability to phosphorylate p53 on Ser392. Surprisingly, C16 was active even in PKR knockdown cells. The ability of C16 to prevent activation of p53 and expression of innate immunity genes may be the source of its strong anti-inflammatory action. Moreover, cells exposed to A + N can influence neighboring cells in paracrine fashion, for instance, they shed ectodomain of COL17A1 protein and induce, in p53-dependent mode, the expression of gene for interleukin-7. Further, the activation of p53 also spurred the expression of SOCS1, an inhibitor of interferon triggered STAT1-dependent signaling. We conclude that, stimulation of p53 primes cells for the production of interferons (through upregulation of STING), and may activate negative-feedback within this signaling system by enhancing the production of SOCS1.

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Section: Treatment With a + N Or Cpt Upregulates Proteins Associated mentioning

confidence: 99%

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

Krześniak

Zajkowicz

Gdowicz-Kłosok

et al. 2020

Cellular Signalling

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“…Moreover, tumor cells can escape immune surveillance cells [4], promoting immune tolerance to the tumor by favoring the establishment of a Th2 immune response, expressing cytokines like IL-4, IL-10, and TGF-β [5]. Previous studies show that a sustained immune change from Th2 to Th1 profiles is critical for tumor cell death [6].…”

Section: Introductionmentioning

confidence: 99%

Antitumor Effect of a Novel Spiro-Acridine Compound is Associated with Up-Regulation of Th1-Type Responses and Antiangiogenic Action

et al. 2019

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Tumor cells have specific features, including angiogenesis induction, cell cycle dysregulation, and immune destruction evasion. By inducing a T helper type 2 (Th2) immune response, tumor cells may favor immune tolerance within the tumor, which allows progression of cancer growth. Drugs with potential antitumor activity are the spiro-acridines, which is a promising new class of acridine compounds. Herein, the novel spiro-acridine (E)-5 -oxo-1 -((3,4,5-trimethoxybenzylidene)amino)-1 ,5 -dihydro-10H-spiro[acridine-9,2 -pyrrole]-4 -carbonitrile (AMTAC-17) was synthesized and tested for antitumor effects. Toxicity evaluation was performed in mice after acute treatment (2000 mg/kg, intraperitoneally, i.p.). The Ehrlich ascites carcinoma model was used to investigate the antitumor activity of AMTAC-17 (12.5, 25, or 50 mg/kg, i.p.) after seven days of treatment. Effects on the cell cycle, angiogenesis, and inflammatory responses were investigated. LD 50 (lethal dose 50%) was estimated to be higher than 5000 mg/kg. AMTAC-17 reduced the Ehrlich tumor's total viable cancer cells count and peritumoral micro-vessels density, and induced an increase in the sub-G1 peak. Additionally, there was an increase of Th1 cytokine profile levels (IL-1β, TNF-α, and IL-12). In conclusion, the spiro-acridine compound AMTAC-17 presents low toxicity, and its in vivo antitumor effect involves modulation of the immune system to a cytotoxic Th1 profile and a reduction of tumor angiogenesis.

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“…The various inflammasomes and inflammatory cytokines and chemokines play contrasting roles in lung, breast, gastric, liver, colon, and prostate cancers and in glioblastomas [44]. Recently, it was reported that Inflammasomes may also exert anticancer effects by specialized programmed cell death called pyroptosis and immune regulatory functions [45]. Our previous work showed that the inflammasome activity was increased in ASH specimens [46].…”

Section: Discussionmentioning

confidence: 99%

The Roles of Epigenetic Regulators and Inflammasome in Hepatocellular Carcinoma Tumorigenesis in Patients with Alcoholic Steatohepatitis (ASH) vs Non-Alcoholic Steatohepatitis (NASH)

Jia¹

2019

COR

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As the fifth most common cancer and the second leading cause of cancer related deaths worldwide, hepatocellular carcinoma (HCC) is an aggressive tumor type with poor prognosis causing 250,000 to one million deaths annually. Alcoholic steatohepatitis (ASH) and non‐alcoholic steatohepatitis (NASH) are the two major growing risk factors and both may develop liver fibrosis or even HCC. However, compared with the rate of patients with ASH progressing to HCC annually, it is much lower in NASH patients. The present study is to clarify the protein expression of epigenetic regulators and Inflammasome components in the oncogenesis pathway between ASH and NASH. By using the immunofluorescence method and morphometrically quantitating the fluorescence intensity in liver biopsied specimens from NASH and ASH patients, we studied the protein expression within hepatocytes cytoplasm of candidate epigenetic regulators G9A and LHPP and inflammasome component ASC. Compared with the control group patients, the expression levels of all three proteins were upregulated in the ASH and NASH group of patients (p < 0.001 in all molecules). While compared with the ASH group of patients, only the expression levels of G9A were significantly lower in the NASH group of patients (p < 0.01). The other two molecules, LHPP and ASC did not change. These results are consistent with our previous work that there are significant differences of many molecules including epigenetic modulators and the inflammasome pathway in both NASH and ASH compared to the control group. Thus, we conclude that there are significantly different molecules and pathways involved during the pathogenesis of HCC development in NASH compared to ASH which may focus the light on developing prevention methods and targeted treatments in NASH and ASH patients. Support or Funding Information This study was funded by NIH/AAA grant # UO‐21898‐05. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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Inflammasomes in Inflammation-Induced Cancer

Cited by 79 publications

References 235 publications

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

Antitumor Effect of a Novel Spiro-Acridine Compound is Associated with Up-Regulation of Th1-Type Responses and Antiangiogenic Action

The Roles of Epigenetic Regulators and Inflammasome in Hepatocellular Carcinoma Tumorigenesis in Patients with Alcoholic Steatohepatitis (ASH) vs Non-Alcoholic Steatohepatitis (NASH)

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