Sapporo Medical University School of Medicine, Department of Pathology, Sapporo, Japan.
Expert Opin Ther Targets. 2012 Sep;16(9):881-7. doi: 10.1517/14728222.2012.708340. Epub 2012 Jul 16.
Pancreatic cancer is one of the most malignant human diseases and there is an urgent need to develop novel diagnostic and therapeutic strategies. Claudin-4, overexpressed in pancreatic cancer and its precursor lesions, is a receptor for Clostridium perfringens enterotoxin (CPE). The cytotoxic effects of CPE and monoclonal antibodies against claudin-4 are useful as novel therapeutic tools for pancreatic cancer.
This review describes and discusses the studies targeting claudin-4 in normal human pancreatic duct epithelial (HPDE) cells and cancer cells.
Claudin-4 is in part regulated via a PKCα signal transduction pathway in pancreatic cancer cell lines. PKCα inhibitors may represent potential therapeutic agents against human pancreatic cancer cells by the use of CPE cytotoxicity via claudin-4. The COOH-terminal half fragment of CPE (C-CPE) enhances the effectiveness of clinically relevant chemotherapies and can be used as a carrier for drugs and other bacterial toxins to claudin-4-positive cancer cells. hTERT-HPDE cells, in which the human telomerase reverse transcriptase (hTERT) gene is introduced into normal HPDE cells, may be a useful model of normal HPDE cells not only for physiological regulation of claudin-4 expression but also for developing safer and more effective therapeutic methods targeting claudin-4 in pancreatic cancer.
胰腺癌是最恶性的人类疾病之一，因此迫切需要开发新的诊断和治疗策略。Claudin-4 在胰腺癌及其前体病变中过度表达，是梭状芽孢杆菌肠毒素 (CPE) 的受体。CPE 和针对 Claudin-4 的单克隆抗体的细胞毒性作用可用作胰腺癌的新型治疗工具。
本文描述并讨论了针对正常人类胰腺导管上皮 (HPDE) 细胞和癌细胞中 Claudin-4 的研究。
Claudin-4 在部分上通过胰腺癌细胞系中的 PKCα 信号转导途径进行调节。PKCα 抑制剂可能通过 Claudin-4 介导的 CPE 细胞毒性作用，代表针对人类胰腺癌细胞的潜在治疗剂。CPE 的 COOH 末端半片段 (C-CPE) 增强了临床相关化疗药物的有效性，并且可以用作携带药物和其他细菌毒素到 Claudin-4 阳性癌细胞的载体。将人类端粒酶逆转录酶 (hTERT) 基因引入正常 HPDE 细胞的 hTERT-HPDE 细胞可能不仅是 Claudin-4 表达的生理调节的有用模型，而且是针对胰腺癌中 Claudin-4 开发更安全、更有效的治疗方法的有用模型。
