title: Therapeutic effect of c-Jun N-terminal kinase inhibition on pancreatic cancer.
abstract: c-Jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) family, and it is reportedly involved in the development of several cancers. However, the role of JNK in pancreatic cancer has not been elucidated. We assessed t he involvement of JNK in the development of pancreatic cancer and investigated the therapeutic effect of JNK inhibitors on this deadly cancer. Small interfering RNAs against JNK or the JNK inhibitor SP600125 were used to examine the role of JNK in cellular proliferation and the cell cycles of pancreatic cancer cell lines. Ptf1a(cre/+) ;LSL-Kras(G12D/+) ;Tgfbr2(flox/flox) mice were treated with the JNK inhibitor to examine pancreatic histology and survival. The effect of JNK inhibition on tumor angiogenesis was also assessed using cell lines and murine pancreatic cancer specimens. JNK was frequently activated in human and murine pancreatic cancer in vitro and in vivo. Growth of human pancreatic cancer cell lines was suppressed by JNK inhibition through G1 arrest in the cell cycle with decreased cyclin D1 expression. In addition, oncogenic K-ras expression led to activation of JNK in pancreatic cancer cell lines. Treatment of Ptf1a(cre/+) ;LSL-Kras(G12D/+) ;Tgfbr2(flox/flox) mice with the JNK inhibitor decreased growth of murine pancreatic cancer and prolonged survival of the mice significantly. Angiogenesis was also decreased by JNK inhibition in vitro and in vivo. In conclusion, activation of JNK promotes development of pancreatic cancer, and JNK may be a potential therapeutic target for pancreatic cancer.
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo.
authors.forename: Ryota
authors.initials: R
authors.lastname: Takahashi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hirata
authors.forename: Kosuke
authors.initials: K
authors.lastname: Sakitani
authors.forename: Wachiko
authors.initials: W
authors.lastname: Nakata
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Yoku
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: Hayato
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Yohko
authors.initials: Y
authors.lastname: Hikiba
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ijichi
authors.forename: Harold L
authors.initials: HL
authors.lastname: Moses
authors.forename: Shin
authors.initials: S
authors.lastname: Maeda
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D020868:Gene Silencing; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality
chemical_list: D000873:Anthracenes; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases