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Preparation of a claudin‐4‐targeted anti‐tumor molecule
Author(s) -
Kondoh Masuo,
Saeki Rie,
Kakutani Hideki,
Hamakubo Takao,
Watari Akihiro,
Yagi Kiyohito
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.964.3
Subject(s) - claudin , cytotoxicity , tight junction , cancer research , cytotoxic t cell , chemistry , microbiology and biotechnology , biology , in vitro , biochemistry
The majority of malignant tumors are derived from epithelial tissues. Tight junctions (TJs) are typical structure of epithelium, and deregulation of TJs is often observed during neoplastic transformation. Claudins are key molecules in formation of TJs; proteins in the 24‐member claudin family contain four transmembrane domains. Claudin‐4 is overexpressed in some human neoplasias, including breast, pancreatic and prostate cancers. These findings indicate that the targeting of claudin‐4 may be a novel strategy for tumor therapy, whereas there are few successes to prepare claudin‐4‐targeting molecule because of its low antigenicity. We previously found that the claudin‐4 binder (C‐CPE) is a novel type of absorption‐enhancer of drug (Mol. Pharmacol., 2005). In the present study, we prepared a claudin‐4–targeting molecule by fusion of C‐CPE with the protein synthesis inhibitory factor (PSIF) derived from Pseudomonas exotoxin. C‐CPE‐PSIF was cytotoxic to claudin‐4‐expressing cells, and pretreatment of the cells with C‐CPE attenuated C‐CPE‐PSIF‐induced cytotoxicity. Mutation of the claudin‐4‐binding domains also attenuated its cytotoxicity. Intratumoral injection of C‐CPE‐PSIF significantly suppressed tumor growth. In contrast, C‐CPEmutant‐PSIF lacking claudin‐4‐binding activity had no effect on tumor growth. These data indicate that a claudin‐4‐targeting may be a potent anti‐tumor strategy.