title: c-Jun N-terminal kinase inhibitor SP600125 enhances barrier function and elongation of human pancreatic cancer cell line HPAC in a Ca-switch model.
abstract: c-Jun N-terminal kinase (JNK), known as a stress-activated protein kinase, regulates normal epithelial biological processes, including assembly of adherens and tight junctions, and it is involved in the development of several cancers. The JNK inhibitor SP600125 enhances epithelial barrier function through modulation of tight junction molecules in normal human pancreatic epithelial cells. Furthermore, this JNK inhibitor suppresses the growth of human pancreatic cancer cells. However, the effects of SP600125 on the epithelial barrier in human pancreatic cancer cells remain unknown. In the present study, the JNK inhibitor SP600125 markedly enhanced the barrier function and cell elongation of well-differentiated human pancreatic cancer cell line HPAC in a Ca-switch model. The epithelial barrier function induced by SP600125 was regulated by phosphorylated β-catenin without changes in the tight junction molecules. The cell elongation induced by SP600125 was closely related to the expression of the F-actin-binding protein DrebrinE. These findings suggest that JNK is involved in the regulation of the epithelial barrier function and cell shape during remodeling of pancreatic cancer cells. The JNK inhibitor SP600125 may have potential as a therapeutic drug for pancreatic cancer via induction of differentiation.
authors.affiliation: Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, S1. W17., Sapporo, 060-8556, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Konno
authors.forename: Takafumi
authors.initials: T
authors.lastname: Ninomiya
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kohno
authors.forename: Shin
authors.initials: S
authors.lastname: Kikuchi
authors.forename: Norimasa
authors.initials: N
authors.lastname: Sawada
authors.forename: Takashi
authors.initials: T
authors.lastname: Kojima
mesh_terms: D000873:Anthracenes / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects*; D048430:Cell Shape / Q000187:drug effects*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D019108:Tight Junctions / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000873:Anthracenes; C495270:CTNNB1 protein, human; D009479:Neuropeptides; D047428:Protein Kinase Inhibitors; D051176:beta Catenin; C053386:drebrins; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D002118:Calcium