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  • Turn a diarrhoea toxin into a receptor-mediated therapy for a plethora of CLDN-4-overexpressing cancers

    Author(s)
    Yao, Qin
    Cao, Siyu
    Li, Chun
    Mengesha, Asferd
    Low, Pauline
    Kong, Beihua
    Dai, Shuzhen
    Wei, Mingqian
    Griffith University Author(s)
    Wei, Ming Q.
    Year published
    2010
    Metadata
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    Abstract
    Molecular targeted therapy (MTT) represents the new generation of anti-cancer arsenals. In this study, we report an alternative approach using a hybrid toxin that utilises the high-affinity of receptor-binding fragment of Clostridium perfringens enterotoxin (CPE). CPE naturally binds to CLDN-4 through the C-terminal 30 amino acid. However, recent studies have shown that CLDN-4 is also overexpressed on a range of cancer cells. We thus constructed a cDNA comprising C-CPE and a well characterised toxic domain of Pseudomonas aeruginosa exotoxin A (C-CPE-ETA'). The recombinant C-CPE-ETA' fusion protein was shown to retain the ...
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    Molecular targeted therapy (MTT) represents the new generation of anti-cancer arsenals. In this study, we report an alternative approach using a hybrid toxin that utilises the high-affinity of receptor-binding fragment of Clostridium perfringens enterotoxin (CPE). CPE naturally binds to CLDN-4 through the C-terminal 30 amino acid. However, recent studies have shown that CLDN-4 is also overexpressed on a range of cancer cells. We thus constructed a cDNA comprising C-CPE and a well characterised toxic domain of Pseudomonas aeruginosa exotoxin A (C-CPE-ETA'). The recombinant C-CPE-ETA' fusion protein was shown to retain the specificity of binding to CLDN-4 and initiating rapid penetration into cytosol in five different CLDN-4 positive cancer cells (Breast-MCF7, Skin-A431, Colon-SW480, Prostate-PC3 and DU145) but not to CLDN-4 negative cells (Hela, HUVEC). C-CPE-ETA' was strongly cytotoxic towards CLDN-4 positive cancer cell, as opposed to cells lacking CLDN-4 expression. Furthermore, we demonstrated that the recombinant fusion protein had significant anti-cancer ability in CLDN-4 positive cancer models in vivo. Subcutaneously implanted MCF7 and SW480 xenograft tumours were significantly decreased or abolished after three repeated injection of the hybrid toxin. Taken together, our results convincingly show that the hybrid toxin targets CLDN-4 positive cancer through receptor-binding, and causes significant tumour cell apoptosis, suggesting its potential as an alternative molecular targeted therapy against a plethora of CLDN-4 positive cancers.
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    Journal Title
    Biochemical and Biophysical Research Communications
    Volume
    398
    Issue
    3
    DOI
    https://doi.org/10.1016/j.bbrc.2010.06.089
    Subject
    Medicinal and biomolecular chemistry
    Biochemistry and cell biology
    Medical biochemistry and metabolomics
    Medical biochemistry and metabolomics not elsewhere classified
    Publication URI
    http://hdl.handle.net/10072/35829
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    • Journal articles

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