Claudin-4: a new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin

Gastroenterology. 2001 Sep;121(3):678-84. doi: 10.1053/gast.2001.27124.


Background & aims: Recently, several members of the claudin family have been identified as integral constituents of tight junctions. Using expression profiling, we previously found claudin-4 to be overexpressed in pancreatic cancer. Because claudin-4 has been described as a receptor for the cytotoxic Clostridium perfringens enterotoxin (CPE), we investigated the effect of CPE on pancreatic cancer cells.

Methods: Expression of claudin-4 was analyzed by Northern blots. In vitro toxicity of CPE was determined by trypan blue exclusion and the (86)Rb-release assay. The in vivo effect of CPE was studied in claudin-4-expressing nude mouse xenografts of the Panc-1 cell line.

Results: Expression analyses showed that claudin-4 was overexpressed in most pancreatic cancer tissues and cell lines and several other gastrointestinal tumors. CPE led to an acute dose-dependent cytotoxic effect, restricted to claudin-4-expressing cells and dependent on claudin-4 expression levels. Furthermore, transforming growth factor beta was identified as a negative modulator of both claudin-4 expression and susceptibility to CPE. In vivo, intratumoral injections of CPE in Panc-1 xenografts led to large areas of tumor cell necrosis and significant reduction of tumor growth.

Conclusions: Our findings suggest that targeting claudin-4-expressing tumors with CPE represents a promising new treatment modality for pancreatic cancer and other solid tumors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / physiopathology
  • Animals
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / physiopathology
  • Claudin-4
  • Dose-Response Relationship, Drug
  • Enterotoxins / pharmacology*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • In Vitro Techniques
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / physiopathology
  • RNA, Messenger / analysis
  • Tight Junctions / physiology
  • Transforming Growth Factor beta / pharmacology
  • Transplantation, Heterologous
  • Tumor Cells, Cultured


  • CLDN4 protein, human
  • Claudin-4
  • Cldn4 protein, mouse
  • Enterotoxins
  • Membrane Proteins
  • RNA, Messenger
  • Transforming Growth Factor beta
  • enterotoxin, Clostridium