The C-terminal fragment of
Clostridium perfringens enterotoxin (C-CPE) modulates the
tight junction protein claudin and disrupts the tight junctional barrier. It also can enhance the effectiveness of
anticancer agents. However, the detailed mechanisms of the effects of C-CPE remain unclear in both normal and cancerous cells. The C-CPE mutant called C-CPE 194 binds only to
claudin-4, but the C-CPE 194 mutant called C-CPE m19 binds not only to
claudin-4 but also to
claudin-1. In the present study, to investigate the mechanisms of the effects of C-CPE on
claudin expression, the tight junctional functions and the cytotoxicity of
anticancer agents, human
pancreatic cancer cells, and normal human pancreatic duct epithelial cells (HPDEs) were treated with C-CPE 194 and C-CPE m19. In well-differentiated cells of the
pancreatic cancer cell line HPAC, C-CPE 194 and C-CPE m19 disrupted both the barrier and fence functions without changes in expression of
claudin-1 and -4, together with an increase of MAPK phosphorylation. C-CPE 194, but not C-CPE m19, enhanced the cytotoxicity of the
anticancer agents gemcitabine and S-1. In poorly differentiated
pancreatic cancer cell line PANC-1, C-CPE 194, but not C-CPE m19, decreased
claudin-4 expression and enhanced MAPK activity and the cytotoxicity of the
anticancer agents. In normal HPDEs, C-CPE 194 and C-CPE m19 decreased
claudin-4 expression and enhanced the MAPK activity, whereas they did not affect the cytotoxicity of the
anticancer agents. Our findings suggest that the
claudin-4 binder C-CPE 194 enhances effects of
anticancer agents on
pancreatic cancer cell lines via a MAPK pathway.