title: Targeting the hedgehog signaling pathway with interacting peptides to Patched-1.
abstract: BACKGROUND
  The hedgehog (Hh) signaling pathway is aberrantly activated in many cancers. Overproduction of sonic hedgehog (Shh), a ligand in the Hh pathway, increases Hh signaling activity by inhibiting Patched-1 (Ptch1), a suppressive receptor in the Hh pathway. The purpose of this study was to establish a novel strategy for treating pancreatic cancer and other Hh-dependent cancers through control of the tumor-suppressive function of Ptch1.
  
  
  METHODS
  We synthesized seven interacting peptides to the amino-acid sequence of the Ptch1 docking site for Shh. Human pancreatic cancer cell lines (AsPC-1, SUIT2) were cultured in the presence or absence of the peptides. Cell proliferation was assessed by cell counting and by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The activity of the Hh pathway was estimated by real-time polymerase chain reaction of the target gene product Gli1. To confirm their anti-tumor activity in vivo, the effect of the peptides in a mouse model of pancreatic cancer was determined. Finally, the Hh signaling activity of the xenograft was examined.
  
  
  RESULTS
  Three of the interacting peptides to Ptch1 suppressed the proliferation of the two pancreatic cancer cell lines and decreased the expression of Gli1, both in vitro and in vivo.
  
  
  CONCLUSIONS
  This study suggests that interacting peptides to Ptch1 may be a new tool for controlling the Hh-dependent growth of pancreatic cancer.
authors.affiliation: Department of Digestive Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki 701-0192, Japan. mnakamura@med.kawasaki-m.ac.jp
authors.forename: Masafumi
authors.initials: M
authors.lastname: Nakamura
authors.forename: Haruo
authors.initials: H
authors.lastname: Tanaka
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Nagayoshi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakashima
authors.forename: Kosuke
authors.initials: K
authors.lastname: Tsutsumi
authors.forename: Takao
authors.initials: T
authors.lastname: Ohtsuka
authors.forename: Shunichi
authors.initials: S
authors.lastname: Takahata
authors.forename: Masao
authors.initials: M
authors.lastname: Tanaka
authors.forename: Hidechika
authors.initials: H
authors.lastname: Okada
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010455:Peptides; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface