The bacterial colicin active against tumor cells in vitro and in vivo is verotoxin 1.

Farkas-Himsley, Hannah; Hill, Richard P.; Rosen, Barry P.; Arab, Sara; Lingwood, Clifford A.

doi:10.1073/pnas.92.15.6996

Cited by 85 publications

(61 citation statements)

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“…Ovarian carcinoma cell lines show particular sensitivity to verotoxin in vitro. Multidrug-resistant (MDR) cell lines, expressing the MDR1 P-glycoprotein (P-gp) drug efflux pump, derived from these cells showed approximately 1000-fold increase in sensitivity to verotoxin in vitro (3). The increase in sensitivity was found to correlate with the increased synthesis of Gb 3 2 isoforms containing shorter fatty acids (4).…”

Section: Verotoxin (Vt)mentioning

confidence: 96%

“…Such tumors showed a noticeable increase in Gb 3 species that migrated more slowly on TLC, consistent with shorter chain fatty acid isoforms. Similarly, human astrocytoma cell lines, which show high sensitivity to verotoxin in vitro (6) and as nude mice xenografts in vivo (7), showed increased content of short chain fatty acid containing Gb 3 . The presence of the short chain fatty acid Gb 3 species was correlated with an altered intracellular trafficking of verotoxin within the sensitive cells, such that toxin was targeted to the endoplasmic reticulum, nuclear envelope, and nucleus, as opposed to the Golgi in cells deficient in such receptor isoforms (4).…”

Section: Verotoxin (Vt)mentioning

confidence: 99%

“…VT was shown to be the active component in a E. coli extract, which showed anticancer activity in several in vitro and in vivo models of neoplasia (3). Ovarian carcinoma cell lines show particular sensitivity to verotoxin in vitro.…”

Section: Verotoxin (Vt)mentioning

confidence: 99%

“…Multidrug-resistant (MDR) cell lines, expressing the MDR1 P-glycoprotein (P-gp) drug efflux pump, derived from these cells showed approximately 1000-fold increase in sensitivity to verotoxin in vitro (3). The increase in sensitivity was found to correlate with the increased synthesis of Gb 3 2 isoforms containing shorter fatty acids (4). Analysis of the neutral glycolipid content of ovarian tumors showed that Gb 3 was elevated for most tumors, but the elevation was markedly greater for metastases and multidrug-resistant tumors (5).…”

Section: Verotoxin (Vt)mentioning

confidence: 99%

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Retroviral Transfection of Madin-Darby Canine Kidney Cells with Human MDR1 Results in a Major Increase in Globotriaosylceramide and 105- to 106-Fold Increased Cell Sensitivity to Verocytotoxin

Lala¹,

Itô²,

Lingwood³

2000

Journal of Biological Chemistry

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Retroviral infection of the Madin-Darby canine kidney (MDCK) renal cell line with human MDR1 cDNA, encoding the P-glycoprotein (P-gp) multidrug resistance efflux pump, induces a major accumulation of the glycosphingolipid (GSL), globotriaosylceramide (Gal␣1-4Gal␤1-4glucosylceramide-Gb 3 ), the receptor for the E. coli-derived verotoxin (VT), to effect a ϳmillion-fold increase in cell sensitivity to VT. The shorter chain fatty acid isoforms of Gb 3 (primarily C16 and C18) are elevated and VT is internalized to the endoplasmic reticulum/nuclear envelope as we have reported for other hypersensitive cell lines. P-gp (but not MRP) inhibitors, e.g. ketoconazole or cyclosporin A (CsA) prevented the increased Gb 3 and VT sensitivity, concomitant with increased vinblastine sensitivity. Gb 3 synthase was not significantly elevated in MDR1-MDCK cells and was not affected by CsA. In MDR1-MDCK cells, synthesis of fluorescent N-[7-(4-nitrobenzo-2-oxa-1,3-diazole)]-aminocaproyl (NBD)-lactosylceramide (LacCer) and NBD-Gb 3 via NBD-glucosylceramide (GlcCer) from exogenous NBD-C 6 -ceramide, was prevented by CsA. We therefore propose that P-gp can mediate GlcCer translocation across the bilayer, from the cytosolic face of the Golgi to the lumen, to provide increased substrate for the lumenal synthesis of LacCer and subsequently Gb 3 . These results provide a molecular mechanism for the observed increased sensitivity of multidrug-resistant tumors to VT and emphasize the potential of verotoxin as an antineoplastic. Two strains (I and II) of MDCK cells, which differ in their glycolipid profile, have been described. The original MDR1-MDCK parental cell was not specified, but the MDR1-MDCK GSL phenotype and glycolipid synthase activities indicate MDCK-I cells. However, the partial drug resistance of MDCK-I cells precludes their being the parental cell. We speculate that the retroviral transfection per se, or the subsequent selection for drug resistance, selected a subpopulation of MDCK-I cells in the parental MDCK-II cell culture and that drug resistance in MDR1-MDCK cells is thus a result of both MDR1 expression and a second, previously unrecognized, component, likely the high level of GlcCer synthesis in these cells.

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Section: Verotoxin (Vt)mentioning

confidence: 96%

Section: Verotoxin (Vt)mentioning

confidence: 99%

Section: Verotoxin (Vt)mentioning

confidence: 99%

Section: Verotoxin (Vt)mentioning

confidence: 99%

See 2 more Smart Citations

Retroviral Transfection of Madin-Darby Canine Kidney Cells with Human MDR1 Results in a Major Increase in Globotriaosylceramide and 105- to 106-Fold Increased Cell Sensitivity to Verocytotoxin

Lala¹,

Itô²,

Lingwood³

2000

Journal of Biological Chemistry

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“…It has been shown that ovarian-derived tumor cells were effectively killed by Stx1, and interestingly, multidrug resistant variants of these tumor cells expressed higher levels of Gb3 and were more sensitive to Stx1 [129]. Gb3 was expressed also in tumor vasculature, suggesting a potential role for Stx as an antiangiogenic agent [130].…”

Section: Exploitation Of Stx In Medicinementioning

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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Intracellular targeting of the endoplasmic reticulum/nuclear envelope by retrograde transport may determine cell hypersensitivity to verotoxin via globotriaosyl ceramide fatty acid isoform traffic

1998

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The pentameric B subunit of verotoxin (VT) mediates the attachment to cell surface globotriaosyl ceramide (Gb3) to facilitate receptor-mediated endocytosis of the toxin. In highly toxin-sensitive tumor cells, the holotoxin and VT1 B subunit is targeted intracellularly to elements of the endoplasmic reticulum (ER)/nuclear membrane. In less sensitive cells, the toxin is targeted to components of the Golgi apparatus. We have studied two cell systems: the induced VT hypersensitivity of human astrocytoma cell lines cultured in the presence of sodium butyrate (compared to sodium propionate and capronate) and the increased VT sensitivity of multiple drug-resistant mutants as compared to parental human ovarian carcinoma cells. In both cases, a difference in the intracellular retrograde transport of the receptor-bound internalized toxin to the ER/nuclear envelope, as opposed to the Golgi, correlated with a >1,000-fold increase in cell sensitivity to VT. This change in intracellular routing may be due to sorting of Gb3 fatty acid isoforms, since nuclear targeting was found in turn to correlate with the preferential synthesis of Gb3 containing shorter chain (primarily C16) fatty acid species. We propose that the isoform-dependent traffic of Gb3 from the cell surface to the ER/nuclear membrane provides a new signal transduction pathway for Gb3 binding proteins.

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The bacterial colicin active against tumor cells in vitro and in vivo is verotoxin 1.

Cited by 85 publications

References 50 publications

Retroviral Transfection of Madin-Darby Canine Kidney Cells with Human MDR1 Results in a Major Increase in Globotriaosylceramide and 105- to 106-Fold Increased Cell Sensitivity to Verocytotoxin

Retroviral Transfection of Madin-Darby Canine Kidney Cells with Human MDR1 Results in a Major Increase in Globotriaosylceramide and 105- to 106-Fold Increased Cell Sensitivity to Verocytotoxin

The Intracellular Journey of Shiga Toxins

Intracellular targeting of the endoplasmic reticulum/nuclear envelope by retrograde transport may determine cell hypersensitivity to verotoxin via globotriaosyl ceramide fatty acid isoform traffic

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