A Novel Tumor-Targeted Therapy Using a Claudin-4-Targeting Molecule

Carcinogenesis is often accompanied by dysfunctional tight junction (TJs), resulting in the loss of cellular polarity. Claudin, a tetra-transmembrane protein, plays a pivotal role in the barrier and fence functions of TJs. Claudin-4 is deregulated in various cancers, including breast, prostate, ovar...

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Published in:Molecular pharmacology 2009-10, Vol.76 (4), p.918-926
Main Authors: Saeki, Rie, Kondoh, Masuo, Kakutani, Hideki, Tsunoda, Shin-Ichi, Mochizuki, Yasuhiro, Hamakubo, Takao, Tsutsumi, Yasuo, Horiguchi, Yasuhiko, Yagi, Kiyohito
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
Base Sequence
Cell Line
Claudin-4
DNA Primers
Female
Membrane Proteins - drug effects
Mice
Mice, Inbred BALB C
Reverse Transcriptase Polymerase Chain Reaction
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Summary:Carcinogenesis is often accompanied by dysfunctional tight junction (TJs), resulting in the loss of cellular polarity. Claudin, a tetra-transmembrane protein, plays a pivotal role in the barrier and fence functions of TJs. Claudin-4 is deregulated in various cancers, including breast, prostate, ovarian, and gastric cancer. Claudin-4 may be a promising target molecule for tumor therapy, but the claudin-targeting strategy has never been fully developed. In the present study, we prepared a claudin-4-targeting molecule by fusion of the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) with the protein synthesis inhibitory factor (PSIF) derived from Pseudomonas aeruginosa exotoxin. PSIF was not cytotoxic to claudin-4-expressing cells, whereas C-CPE-PSIF was cytotoxic. Cells that express claudin-1, -2, and -5 were less sensitive to C-CPE-PSIF. Pretreatment of the cells with C-CPE attenuated C-CPE-PSIF-induced cytotoxicity, and mutation of C-CPE in the claudin-4-binding residues attenuated the cytotoxicity of C-CPE-PSIF. TJ-undeveloped cells were more sensitive to C-CPE-PSIF than TJ-developed cells. It is noteworthy that polarized epithelial cells are sensitive to C-CPE-PSIF applied to the basal side, whereas the cells were less sensitive to C-CPE-PSIF applied to the apical side. Intratumoral injection of C-CPE-PSIF reduced tumor growth. This is the first report to indicate that a claudin-4-targeting strategy may be a promising method to overcome the malignant tumors.
ISSN:0026-895X
1521-0111
DOI:10.1124/mol.109.058412