Clostridium perfringens Enterotoxin Utilizes Two Structurally Related Membrane Proteins as Functional Receptors in Vivo

Katahira, Jun; Sugiyama, Hiromu; Inoue, Norimitsu; Horiguchi, Yasuhiko; Matsuda, Morihiro; Sugimoto, Nakaba

doi:10.1074/jbc.272.42.26652

Cited by 247 publications

(201 citation statements)

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“…[20][21][22] CPE binds to a subset of the claudin family of tight junction proteins, such as claudin-3 and -4, initially defined as CPE receptors. 23 The C-terminus of CPE permits this binding, whereas the N-terminus of CPE is rather associated with cytotoxicity. 24,25 CPE preferentially binds to claudin-4 and with lower affinity to claudin-3.…”

Section: Introductionmentioning

confidence: 99%

“…24,25 CPE preferentially binds to claudin-4 and with lower affinity to claudin-3. 23,26 Claudin-3 and -4 regulate paracellular permeability, maintain epithelial cell polarity and are often overexpressed in epithelial tumors, such as colon, breast, pancreas, prostate, ovarian or endometrial cancer. [27][28][29][30][31][32] Thus, particularly these two claudins are attractive targets for the selective CPE treatment of solid tumors.…”

Section: Introductionmentioning

confidence: 99%

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Novel Clostridium perfringens enterotoxin suicide gene therapy for selective treatment of claudin-3- and -4-overexpressing tumors

et al. 2011

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Bacterial toxins are known to be effective for cancer therapy. Clostridium perfringens enterotoxin (CPE) is produced by the bacterial Clostridium type A strain. The transmembrane proteins claudin-3 and -4, often overexpressed in numerous human epithelial tumors (for example, colon, breast, pancreas, prostate and ovarian), are the targeted receptors for CPE. CPE binding to them triggers formation of membrane pore complexes leading to rapid cell death. In this study, we aimed at selective tumor cell killing by CPE gene transfer. We generated expression vectors bearing the bacterial wild-type CPE cDNA (wtCPE) or translationoptimized CPE (optCPE) cDNA for in vitro and in vivo gene therapy of claudin-3-and -4-overexpressing tumors. The CPE expression analysis at messenger RNA and protein level revealed more efficient expression of optCPE compared with wtCPE. Expression of optCPE showed rapid cytotoxic activity, hightened by CPE release as bystander effect. Cytotoxicity of up to 100% was observed 72 h after gene transfer and is restricted to claudin-3-and -4-expressing tumor lines. MCF-7 and HCT116 cells with high claudin-4 expression showed dramatic sensitivity toward CPE toxicity. The claudin-negative melanoma line SKMel-5, however, was insensitive toward CPE gene transfer. The non-viral intratumoral in vivo gene transfer of optCPE led to reduced tumor growth in MCF-7 and HCT116 tumor-bearing mice compared with the vector-transfected control groups. This novel approach demonstrates that CPE gene transfer can be employed for a targeted suicide gene therapy of claudin-3-and -4-overexpressing tumors, leading to the rapid and efficient tumor cell killing in vitro and in vivo.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel Clostridium perfringens enterotoxin suicide gene therapy for selective treatment of claudin-3- and -4-overexpressing tumors

et al. 2011

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“…Protéine CPE-R (22.029 kDa) [81,82] (types A, D et C) Par ailleurs, des entérotoxines reconnaissent des sites sur de simples lipides membranaires (le cholestérol, les phospholipides, tels que la phosphatidylcholine, et les sphingolipides, tels que la sphingomyéline). Dans la plupart des cas, ce sont les toxines endommageant la membrane plasmique.…”

Section: Entérotoxine Cpeunclassified

“…CPE semble agir sur les cellules épithéliales par un méca-nisme en plusieurs étapes : attachement avec la surface cellulaire, insertion membranaire, puis formation d'un pore perméable aux ions [60,102,142]. Le pore est constitué d'un hétérocomplexe entre la molécule de toxine et deux protéines membranaires de 70 et 50 kDa [82,162,163]. L'attachement et l'insertion membranaire sont des étapes indépendantes des cations divalents, alors que les étapes consécutives sont dépendantes du calcium [133].…”

Section: Formation De Pores Membranairesunclassified

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Les récepteurs des entérotoxines bactériennes

Rousset

2000

Vet. Res.

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-Bacterial enterotoxin receptors. Enteric bacterial toxins display a great diversity in their structure, molecular weight and mechanism of action. The interaction of enterotoxins with the intestinal mucosa either leads to a direct effect on the cell membrane or an effect on signal transduction within eukaryotic cells. However, before a toxin can affect a cell, it must after its secretion by a microorganism, recognise and bind to a specific surface molecule, its receptor. Membrane receptors of bacterial enterotoxins have been identified as protein, glycoprotein or glycolipid in nature. The chemical nature of the molecules acting as receptors is crucial and during evolution they have been carefully selected. Some toxins, after their interaction with a receptor molecule, will transduce a signal across the cell membrane while remaining at the cell surface. Other toxins, after this initial binding step with a receptor, will be internalised. Others can form pores leading to leakage of cellular components and cell lysis. Receptors that have been identified often comprise a saccharidic chain that is directly involved in the recognition and binding of the toxin. Today, models explaining toxin-receptor interactions are more complex, including multistep events. This review summarises the knowledge of the interactions between bacterial toxins and membrane receptors present on intestinal mucosa. receptor / intestine / enterotoxin / binding epitope / glycosphingolipidRésumé -Les toxines bactériennes entériques présentent une grande diversité autant dans leur structure que dans leur poids moléculaire et leur mécanisme d'action. L'interaction des entérotoxines avec la muqueuse intestinale conduit soit à un effet direct sur la paroi cellulaire de la cellule hôte, soit à un dérèglement des voies de signalisation de celle-ci. Toutefois, avant même d'affecter la cellule cible, la toxine sécrétée par le micro-organisme devra reconnaître et s'attacher à une molécule présente à la surface cellulaire, son récepteur. Les récepteurs membranaires des entérotoxines bactériennes peuvent être de nature protéique, glycoprotéique ou glycolipidique. La nature chimique de ces récepteurs, sur laquelle repose la spécificité, est primordiale et au cours de l'évolution ceuxci ont été soigneusement sélectionnés. Certaines toxines, une fois en contact avec leur récepteur, envoient un signal à l'intérieur de la cellule tout en demeurant à la surface alors que d'autres toxines sont internalisées. Enfin, certaines toxines bactériennes peuvent former des pores dans la membrane Vet. Res. 31 (2000)

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Overexpression of claudin‐3 and claudin‐4 receptors in uterine serous papillary carcinoma

Santin

Bellone

Marizzoni

et al. 2007

Cancer

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BACKGROUND.Uterine serous papillary carcinoma (USPC) represents a highly aggressive variant of endometrial cancer. Using gene expression profiling, we recently identified high expression of the claudin‐3 and claudin‐4 receptors in a limited set of USPC. These tight junction proteins represent the low‐ and high‐affinity receptors, respectively, for the cytotoxic Clostridium perfringens enterotoxin (CPE) and are sufficient to mediate CPE binding and trigger subsequent toxin‐mediated cytolysis. The potential for targeting this pathway in the treatment of USPC was explored.METHODS.Claudin‐3 and claudin‐4 receptor expression was analyzed at the mRNA and protein levels in flash‐frozen and formalin‐fixed, paraffin‐embedded tissue from 20 consecutive USPC patients. The potential of recombinant CPE as a novel therapy against primary, metastatic, and chemotherapy‐resistant USPC cell lines was also investigated in vitro. Finally, the in vivo therapeutic effect of sublethal doses of CPE was studied in SCID mouse xenografts harboring subcutaneous and intraperitoneal USPC that expressed claudin‐3 and claudin‐4.RESULTS.In all, 100% (20 out of 20) of the primary flash‐frozen USPC tested overexpressed 1 or both CPE receptors by quantitative reverse‐transcriptase polymerase chain reaction (RT‐PCR). Membranous immunoreactivity for claudin‐4 protein expression was documented in the majority of USPC specimens tested by immunohistochemistry, whereas only a low level of membranous staining was found in normal endometrial control tissue samples. When primary and metastatic short‐term USPC cell lines were incubated with different concentrations of CPE in vitro, a dose‐dependent cytotoxic effect was demonstrated. In vivo, intratumoral injections of well‐tolerated doses of CPE in large subcutaneous USPC xenografts led to large areas of tumor cell necrosis and tumor disappearance in all the treated animals, whereas sublethal intraperitoneal injections of CPE had a significant inhibitory effect on tumor progression, with extended survival of animals harboring chemotherapy‐resistant intra‐abdominal USPC carcinomatosis.CONCLUSIONS.Claudin‐3 and claudin‐4 receptors may offer promising targets for the use of CPE as a novel type‐specific therapy against this highly aggressive and chemotherapy‐resistant variant of endometrial cancer. Cancer 2007. © 2007 American Cancer Society.

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Clostridium perfringens Enterotoxin Utilizes Two Structurally Related Membrane Proteins as Functional Receptors in Vivo

Cited by 247 publications

References 24 publications

Novel Clostridium perfringens enterotoxin suicide gene therapy for selective treatment of claudin-3- and -4-overexpressing tumors

Novel Clostridium perfringens enterotoxin suicide gene therapy for selective treatment of claudin-3- and -4-overexpressing tumors

Les récepteurs des entérotoxines bactériennes

Overexpression of claudin‐3 and claudin‐4 receptors in uterine serous papillary carcinoma

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