A Novel Tumor-Targeted Therapy Using a Claudin-4-Targeting Molecule
A Novel Tumor-Targeted Therapy Using a Claudin-4-Targeting Molecule
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DOI：
10.1124/mol.109.058412
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发表时间：
2009-10-01
影响因子：
3.6
通讯作者：
Yagi, Kiyohito
中科院分区：
文献类型：
--
作者：
Saeki, Rie;Kondoh, Masuo;Yagi, Kiyohito
癌变通常伴随着紧密连接（TJ）功能失调，导致细胞极性丧失。 Claudin 是一种四跨膜蛋白，在 TJ 的屏障和栅栏功能中发挥着关键作用。 Claudin-4 在多种癌症中失调，包括乳腺癌、前列腺癌、卵巢癌和胃癌。 Claudin-4 可能是一种有前景的肿瘤治疗靶分子，但 Claudin 靶向策略尚未完全开发出来。在本研究中，我们通过将产气荚膜梭菌肠毒素（C-CPE）的C端片段与铜绿假单胞菌外毒素衍生的蛋白质合成抑制因子（PSIF）融合，制备了claudin-4靶向分子。 PSIF 对表达claudin-4 的细胞没有细胞毒性，而C-CPE-PSIF 有细胞毒性。表达claudin-1、-2和-5的细胞对C-CPE-PSIF不太敏感。用C-CPE预处理细胞减弱了C-CPE-PSIF诱导的细胞毒性，而claudin-4结合残基中C-CPE的突变减弱了C-CPE-PSIF的细胞毒性。 TJ 未发育的细胞比 TJ 发育的细胞对 C-CPE-PSIF 更敏感。值得注意的是，极化上皮细胞对应用于基底侧的 C-CPE-PSIF 敏感，而细胞对应用于顶端侧的 C-CPE-PSIF 不太敏感。瘤内注射 C-CPE-PSIF 可减少肿瘤生长。这是第一份表明claudin-4靶向策略可能是克服恶性肿瘤的有希望的方法的报告。
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.