Dataset Information

Shiga-like toxin I exerts specific and potent anti-tumour efficacy against gastric cancer cell proliferation when driven by tumour-preferential Frizzled-7 promoter.

ABSTRACT:

Objectives

Tumour-targeted gene therapy is a promising approach for effective control of gastric cancer cell proliferation. Our study aims to develop a cancer therapy which combines tumour-targeting promoters with cytotoxins.

Methods

The expression of globotriaosylceramide (Gb3), which is a Shiga-like toxin I (Stx1) receptor, was verified in gastric cancer compared with normal stomach tissues as assessed by flow cytometry and immunohistochemical analysis. We therefore constructed the recombinant pFZD7-Stx1 plasmid vectors with tumour-preferential Frizzled-7 promoter and Stx1. pFZD7-Stx1 was used to treat gastric cancer in vitro and in vivo. The gastric cancer cell proliferation and tumour growth were identified after the transfection with the pFZD7-Stx1.

Results

Globotriaosylceramide was obviously increased in gastric cancer compared with normal stomach. The gastric cancer cell proliferation and tumour growth decreased significantly after the transfection with the pFZD7-Stx1.

Conclusion

Frizzled-7 promoter is preferentially active, and Gb3 is abundant in gastric cancer cells. Frizzled-7 promoter and Stx1 may be used to determine a novel and relatively specific and potent gastric cancer therapeutic strategy.

SUBMITTER: Xu H

PROVIDER: S-EPMC6536451 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Shiga-like toxin I exerts specific and potent anti-tumour efficacy against gastric cancer cell proliferation when driven by tumour-preferential Frizzled-7 promoter.

Xu Hongpan H Peng Lijun L Shen Mengjiao M Xia Yanyan Y Li Zhiyang Z He Nongyue N

Cell proliferation 20190406 3

<h4>Objectives</h4>Tumour-targeted gene therapy is a promising approach for effective control of gastric cancer cell proliferation. Our study aims to develop a cancer therapy which combines tumour-targeting promoters with cytotoxins.<h4>Methods</h4>The expression of globotriaosylceramide (Gb3), which is a Shiga-like toxin I (Stx1) receptor, was verified in gastric cancer compared with normal stomach tissues as assessed by flow cytometry and immunohistochemical analysis. We therefore constructed ...[more]

PMID: 30955216

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Project description:Bacillus anthracis causes anthrax through a combination of bacterial infection and toxemia. As a major virulence factor of B. anthracis, anthrax lethal toxin (LT) is a zinc-dependent metalloproteinase, exerting its cytotoxicity through proteolytic cleavage of the mitogen-activated protein kinase kinases, thereby shutting down the MAPK pathways. Anthrax lethal toxin induces host lethality mostly by targeting the cardiovascular system. Although the enzymatic activity and the molecular targets of LT have long been known, the detailed mechanisms underlying cellular/tissue/organ toxicity are still poorly understood. In this work, we sought to investigate the mechanism of LT-induced cellular damage in the cardiovascular system. We demonstrate for the first time that anthrax lethal toxin has potent inhibitory effects on the central metabolism of cardiomyocytes and endothelial cells. This is likely due to the observed downregulating of c-Myc expression through the toxin-induced inhibition of the ERK pathway. Since c-Myc is a master transcription factor controlling the expression of many rate-limiting metabolic enzymes in glycolysis and the tricarboxylic acid cycle, LT's downregulation of c-Myc may lead to the observed bioenergetic collapse, particularly, in cardiomyocytes. Since cardiac cell contraction requires continuous production of large amounts of ATP, potent inhibition of the bioenergetics of cardiomyocytes would be incompatible with life. Thus, LT-induced lethality through targeting cardiomyocytes and endothelial cells appears to be a consequence of a bioenergetic collapse, likely due to the toxin's potent inhibitory activity on the MEK-ERK-c-Myc-metabolic/bioenergetic axis within these target cells of cardiovascular system.IMPORTANCEAnthrax lethal toxin (LT) is a major virulence factor of Bacillus anthracis, the causative pathogen of anthrax disease. Anthrax lethal toxin is a metalloproteinase that cleaves and inactivates MEKs, thereby shutting down MAPK pathways, leading to host mortality primarily through targeting of the cardiovascular system. However, the detailed mechanisms underlying the toxin's cellular and tissue toxicity are still poorly understood. Here, we found that anthrax lethal toxin has potent inhibitory activity on glycolysis and oxidative phosphorylation of cardiomyocytes and endothelial cells. These effects appear to be the consequence of downregulation of c-Myc, a master transcription factor that controls many rate-limiting enzymes of glycolysis and the tricarboxylic acid cycle. With the high demand on energy for cardiac contraction, the potent inhibition of cardiomyocyte metabolism by LT would be incompatible with life. This work provides critical insights into why the cardiovascular system is the major in vivo target of LT-induced lethality.

Dataset Information

Shiga-like toxin I exerts specific and potent anti-tumour efficacy against gastric cancer cell proliferation when driven by tumour-preferential Frizzled-7 promoter.

Objectives

Methods

Results

Conclusion

Publications

Shiga-like toxin I exerts specific and potent anti-tumour efficacy against gastric cancer cell proliferation when driven by tumour-preferential Frizzled-7 promoter.

Similar Datasets

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