title: A novel tumor-targeted therapy using a claudin-4-targeting molecule.
abstract: 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.
authors.affiliation: Laboratory of Bio-Functional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Saeki
authors.forename: Masuo
authors.initials: M
authors.lastname: Kondoh
authors.forename: Hideki
authors.initials: H
authors.lastname: Kakutani
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Tsunoda
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Mochizuki
authors.forename: Takao
authors.initials: T
authors.lastname: Hamakubo
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Tsutsumi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Horiguchi
authors.forename: Kiyohito
authors.initials: K
authors.lastname: Yagi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D002460:Cell Line; D062506:Claudin-4; D017931:DNA Primers; D005260:Female; D008565:Membrane Proteins / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D062506:Claudin-4; C568158:Cldn4 protein, mouse; D017931:DNA Primers; D008565:Membrane Proteins