Two Distinct Gb3/CD77 Signaling Pathways Leading to Apoptosis Are Triggered by Anti-Gb3/CD77 mAb and Verotoxin-1

Tétaud, Cécile; Falguières, Thomas; Carlier, Karine; Lécluse, Yann; Garibal, Julie; Coulaud, Dominique; Busson, P.; Steffensen, Rudi; Clausen, Henrik; Johannes, Ludger; Wiels, Joëlle

doi:10.1074/jbc.m303868200

Cited by 73 publications

(80 citation statements)

References 47 publications

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“…In our present study, we used only the nontoxic STxB. It has been shown by several studies that STxB is capable of apoptosis induction in Burkitt's lymphoma cells, although it is not able to inhibit protein synthesis (33,36,38).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies showed that human intestinal epithelium (11,15) and purified epithelial cells (12,33,34) were Gb 3 -negative. In agreement with these studies, we found that normal human colonocytes were not labeled by STxB, and in our previous in vivo experiments on mice, STxB did not accumulate in these cells (30).…”

Section: Discussionmentioning

confidence: 99%

“…Two independent pathways have been reported, at least in cells of lymphoid origin, that lead to apoptosis upon binding of either the holotoxin or a specific antibody to Gb 3 /CD77 (33). Therefore, we have compared in parallel the effects of a specific anti-CD77 antibody with the uptake of STxB on primary colon cancer cells.…”

Section: Uptake Of Stxb By Primary Tumor Cellsmentioning

confidence: 99%

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Human colorectal tumors and metastases express Gb3 and can be targeted by an intestinal pathogen-based delivery tool

Falguières

Maak

Weyhern

et al. 2008

Molecular Cancer Therapeutics

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The targeting of solid tumors requires delivery tools that resist intracellular and extracellular inactivation, and that are taken up specifically by tumor cells. We have shown previously that the recombinant nontoxic B-subunit of Shiga toxin (STxB) can serve as a delivery tool to target digestive tumors in animal models. The aim of this study was to expand these experiments to human colorectal cancer. Tissue samples of normal colon, benign adenomas, colorectal carcinomas, and liver metastases from 111 patients were obtained for the quantification of the expression of the cellular STxB receptor, the glycosphingolipid globotriaosyl ceramide (Gb 3 or CD77). We found that compared with normal tissue, the expression of Gb 3 was strongly increased in colorectal adenocarcinomas and their metastases, but not in benign adenomas. Short-term primary cultures were prepared from samples of 43 patients, and STxB uptake was studied by immunofluorescence microscopy. Of a given tumor sample, on average, 80% of the cells could visibly bind STxB, and upon incubation at 37°C, STxB was transported to the Golgi apparatus, following the retrograde route. This STxB-specific intracellular targeting allows the molecule to avoid recycling and degradation, and STxB could consequently be detected on tumor cells even 5 days after initial uptake. In conclusion, the targeting properties of STxB could be diverted for the delivery of contrast agents to human colorectal tumors and their metastases, whose early detection and specific targeting remains one of the principal challenges in oncology. [Mol Cancer Ther 2008;7(8):2498 -508]

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Uptake Of Stxb By Primary Tumor Cellsmentioning

confidence: 99%

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Human colorectal tumors and metastases express Gb3 and can be targeted by an intestinal pathogen-based delivery tool

Falguières

Maak

Weyhern

et al. 2008

Molecular Cancer Therapeutics

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“…Nevertheless, it has been known that holotoxin initial internalization will be A subunit-independent, and two pathways have been identified as applicable to holotoxin endocytosis (Khine et al 2004). Moreover, two distinct Gb3/ CD77 signaling pathways leading to apoptosis have been triggered by Anti-Gb3/CD77 mAb and Stx (Tétaud et al 2003). Therefore, different intracellular routing may play a pivotal role in cell susceptibility and triggering a different pathway for apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Study on induction of apoptosis on HeLa and Vero cells by recombinant shiga toxin and its subunits

2009

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Verotoxin (VT) or shiga toxin (Stx) produced by enterohemorrhagic Escherichia coli (EHEC) and Shigella dysenteriae is AB5 holotoxin with potent protein synthesis inhibitor. VT can induce both apoptosis and necrosis depending on the cell type, it has been shown that VT-induced apoptosis and cytotoxicity are distinct processes, and the A subunit can be necessary for apoptosis. In other words, the precise role of each subunit in apoptosis signaling has yet to be established. In this study, induction of apoptosis has been examined by using both recombinant A and B subunits, and recombinant Stx (rStx) with different doses in HeLa and Vero cells. For this purpose, the polymyxin B extract of constructs expressing A, B and AB5 recombinant proteins was used. Therefore, amounts greater than normally reported were used to induce desire effects on cell lines. The apoptotic effect of A and B subunits appear at higher doses than that of rStx. The highest apoptotic effect was observed for rStx at low concentration, compared to A and B subunits. A or B subunits separately cannot induce the signaling pathway stimulated by holotoxin though A subunit, does induce laddering pattern similar to holotoxin. We concluded that both subunits are important in complete death signaling pathway. Since different concentration of A and B subunits and rStx was required in different assay, therefore, it could be emphasized that cell death or even apoptosis caused by either of the subunits or holotoxin depends on sensitivity or specificity of the assay and cell types used.

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“…In some cell types the Shiga toxins, as a long term effect, induce expression and secretion of pro-inflammatory cytokines, including TNF-, IL-1, IL-6 and IL-8 [6,11,12]. Interestingly, the secreted cytokines can induce synthesis of Gb3 in other cell types, thereby sensitizing these cells to the toxin [13].…”

Section: Introductionmentioning

confidence: 99%

The Intracellular Journey of Shiga Toxins

Torgersen¹

2013

TOTNJ

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Abstract:The Shiga toxin family consists of Shiga toxin (Stx) that is produced as a virulence factor by Shigella dysenteriae, and the Shiga-like toxins produced by certain strains of enterohemorrhagic E. coli as well as by some other types of bacteria. Infection with bacteria producing these toxins is a threat to human health even in industrialized countries, as the initial diarrhea caused by the infection might be followed by a complication named hemolytic uremic syndrome. The Shiga toxins consist of a binding moiety that in most cases binds to the glycosphingolipid Gb3 on the surface of susceptible cells, and an A-moiety responsible for the toxic effect in the cytosol. In order to reach its cytosolic target, the toxin must be internalized and then transported via the retrograde pathway to the Golgi complex and further to the endoplasmic reticulum. From the endoplasmic reticulum the enzymatically active part of the A-moiety is translocated to the cytosol, and cellular protein synthesis is inhibited. Although the Shiga toxins are involved in disease, they may also be exploited for medical diagnosis and treatment. Interestingly, the toxin receptor, Gb3, has a limited expression in normal tissues, but is overexpressed in several types of cancer. Thus, the use of Shiga toxin, or the binding part of the toxin, has great potential in cancer diagnostics and treatment. Furthermore, studies of the various uptake mechanisms and intracellular transport pathways exploited by the toxins, provide important insight in basic cell biology processes.

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Two Distinct Gb3/CD77 Signaling Pathways Leading to Apoptosis Are Triggered by Anti-Gb3/CD77 mAb and Verotoxin-1

Cited by 73 publications

References 47 publications

Human colorectal tumors and metastases express Gb3 and can be targeted by an intestinal pathogen-based delivery tool

Human colorectal tumors and metastases express Gb3 and can be targeted by an intestinal pathogen-based delivery tool

Study on induction of apoptosis on HeLa and Vero cells by recombinant shiga toxin and its subunits

The Intracellular Journey of Shiga Toxins

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