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Secreting-lux/pT-ClyA engineered bacteria suppresses tumor growth via interleukin-1β in two pathways.

ABSTRACT: Engineered Salmonella typhimurium (S.t-ΔpG^lux/pT-ClyA) and attenuated Salmonella typhimurium (SL: Salmonella typhimurium with a defect in the synthesis of guanine 5'-diphosphate-3'-diphosphate) exhibit similar tumor targeting capabilities (Kim et al. in Theranostics 5:1328-1342, 2015; Jiang et al. in Mol Ther 18:635-642, 2013), but S.t-ΔpG^lux/pT-ClyA exerts superior tumor suppressive effects. The aim of this study was to investigate whether S.t-ΔpG^lux/pT-ClyA inhibits colon cancer growth and recurrence by promoting increased IL-1β production. The CT26 tumor mouse model was used, and mice were treated in the following ways: PBS, S.t-ΔpG^{lux/pT-ClyA(+)} + IL-1βAb, SL, S.t-ΔpG^{lux/pT-ClyA(-)}, and S.t-ΔpG^{lux/pT-ClyA(+)}. Dynamic evaluation of the efficacy of S.t-ΔpG^lux/pT-ClyA in the treatment of colon cancer was assessed by MRI. Western blot, immunofluorescence and flow cytometry analysis were used to investigate IL-1β-derived cells and IL-1β expression on tumor cells and immune cells to analyze the regulatory mechanism. IL-1β levels in tumors colonized by S.t-ΔpG^lux/pT-ClyA were significantly increased and maintained at high levels compared to control treatments. This increase caused tumors to subside without recurrence. We examined the immune cells mediating S.t-ΔpG^lux/pT-ClyA-induced tumor suppression and examined the major cell types producing IL-1β. We found that macrophages and dendritic cells were the primary IL-1β producers. Inhibition of IL-1β in mice treated with S.t-ΔpG^lux/pT-ClyA using an IL-1β antibody caused tumor growth to resume. This suggests that IL-1β plays an important role in the treatment of cancer by S.t-ΔpG^lux/pT-ClyA. We found that in St-ΔpG^lux/pT-ClyA-treated tumors, expression of molecules involved in signaling pathways, such as NLRP3, ASC, Caspase1, TLR4, MyD88, NF-kB and IL-1β, were upregulated, while in ΔppGpp S. typhimurium treated animals, TLR4, MyD88, NF-kB and IL-1β were upregulated with NLRP3, ASC, and Caspase1 being rarely expressed or not expressed at all. Using S.t-ΔpG^lux/pT-ClyA may simultaneously activate TLR4 and NLRP3 signaling pathways, which increase IL-1β expression and enhance inhibition of colon cancer growth without tumor recurrence. This study provides a novel platform for treating colon cancer.

SUBMITTER: Wu Y

PROVIDER: S-EPMC6872689 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Secreting-lux/pT-ClyA engineered bacteria suppresses tumor growth via interleukin-1β in two pathways.

Wu Yuqin Y Feng Zhicai Z Jiang Shengnan S Chen Jing J Zhan Yuefu Y Chen Jianqiang J

AMB Express 20191121 1

Engineered Salmonella typhimurium (S.t-ΔpGlux/pT-ClyA) and attenuated Salmonella typhimurium (SL: Salmonella typhimurium with a defect in the synthesis of guanine 5'-diphosphate-3'-diphosphate) exhibit similar tumor targeting capabilities (Kim et al. in Theranostics 5:1328-1342, 2015; Jiang et al. in Mol Ther 18:635-642, 2013), but S.t-ΔpGlux/pT-ClyA exerts superior tumor suppressive effects. The aim of this study was to investigate whether S.t-ΔpGlux/pT-ClyA inh ...[more]

PMID: 31754923

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Project description:Duchenne muscular dystrophy (DMD) is a severe X-linked recessive muscle disorder caused by mutations in the dystrophin gene. Nonetheless, secondary processes involving perturbation of muscle regeneration probably exacerbate disease progression, resulting in the fatal loss of muscle in DMD patients. A dysfunction of undifferentiated myogenic cells is the most likely cause for the reduction of regenerative capacity of muscle. To clarify molecular mechanisms in perturbation of the regenerative capacity of DMD muscle, we have established several NCAM (CD56)-positive immortalized human dystrophic and non-dystrophic myogenic cell lines from DMD and healthy muscles. A pro-inflammatory cytokine, IL-1β, promoted cell cycle progression of non-dystrophic myogenic cells but not DMD myogenic cells. In contrast, IL-1β upregulated the Notch ligand Jagged1 gene in DMD myogenic cells but not in non-dystrophic myogenic cells. Knockdown of Jagged1 in DMD myogenic cells restored the IL-1β-promoted cell cycle progression. Conversely, enforced expression of Jagged1-blocked IL-1β promoted proliferation of non-dystrophic myogenic cells. In addition, IL-1β prevented myogenic differentiation of DMD myogenic cells depending on Jagged1 but not of non-dystrophic myogenic cells. These results demonstrate that Jagged1 induced by IL-1β in DMD myogenic cells modified the action of IL-1β and reduced the ability to proliferate and differentiate. IL-1β induced Jagged1 gene expression may be a feedback response to excess stimulation with this cytokine because high IL-1β (200-1000 pg/ml) induced Jagged1 gene expression even in non-dystrophic myogenic cells. DMD myogenic cells are likely to acquire the susceptibility of the Jagged1 gene to IL-1β under the microcircumstances in DMD muscles. The present results suggest that Jagged1 induced by IL-1β plays a crucial role in the loss of muscle regeneration capacity of DMD muscles. The IL-1β/Jagged1 pathway may be a new therapeutic target to ameliorate exacerbation of muscular dystrophy in a dystrophin-independent manner.

Dataset Information

Secreting-lux/pT-ClyA engineered bacteria suppresses tumor growth via interleukin-1β in two pathways.

Publications

Secreting-lux/pT-ClyA engineered bacteria suppresses tumor growth via interleukin-1β in two pathways.

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