Turn a diarrhoea toxin into a receptor-mediated therapy for a plethora of CLDN-4-overexpressing cancers.
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.
Yao
Qin
Q
Division of Molecular and Gene Therapies, School of Medical Science, Griffith University, Gold Coast Campus, Southport, Qld 4215, Australia.
Cao
Siyu
S
Li
Chun
C
Mengesha
Asferd
A
Low
Pauline
P
Kong
Beihua
B
Dai
Shuzhen
S
Wei
Mingqian
M
D036002:ADP Ribose Transferases / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D062506:Claudin-4; D004768:Enterotoxins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D005098:Exotoxins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D062506:Claudin-4; D004768:Enterotoxins; D005098:Exotoxins; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C568157:CLDN4 protein, human; C568158:Cldn4 protein, mouse; C035598:enterotoxin, Clostridium