title: Claudin-4 binder C-CPE 194 enhances effects of anticancer agents on pancreatic cancer cell lines via a MAPK pathway.
abstract: 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.
authors.affiliation: Department of Surgery Sapporo Medical University School of Medicine Sapporo Japan; Department of Cell Science Research Institute for Frontier Medicine Sapporo Medical University School of Medicine Sapporo Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kono
authors.affiliation: Laboratory of Bio-Functional Molecular Chemistry Graduate School of Pharmaceutical Sciences Osaka University Suita Japan.
authors.forename: Masuo
authors.initials: M
authors.lastname: Kondoh
authors.affiliation: Department of Surgery Sapporo Medical University School of Medicine Sapporo Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kyuno
authors.affiliation: Department of Surgery Sapporo Medical University School of Medicine Sapporo Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ito
authors.affiliation: Department of Surgery Sapporo Medical University School of Medicine Sapporo Japan.
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Kimura
authors.affiliation: Department of Surgery Sapporo Medical University School of Medicine Sapporo Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Imamura
authors.affiliation: Department of Cell Science Research Institute for Frontier Medicine Sapporo Medical University School of Medicine Sapporo Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kohno
authors.affiliation: Department of Cell Science Research Institute for Frontier Medicine Sapporo Medical University School of Medicine Sapporo Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Konno
authors.affiliation: Department of Surgery Sapporo Medical University School of Medicine Sapporo Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Furuhata
authors.affiliation: Department of Pathology Sapporo Medical University School of Medicine Sapporo Japan.
authors.forename: Norimasa
authors.initials: N
authors.lastname: Sawada
authors.affiliation: Department of Surgery Sapporo Medical University School of Medicine Sapporo Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Hirata
authors.affiliation: Department of Cell Science Research Institute for Frontier Medicine Sapporo Medical University School of Medicine Sapporo Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kojima
keywords: C‐CPE; MAPK; claudins; human pancreatic duct epithelial cells; pancreatic cancer; tight junctions