Targeting the hedgehog signaling pathway with interacting peptides to Patched-1

Masafumi Nakamura, Haruo Tanaka, Yousuke Nagayoshi, Hiroshi Nakashima, Kosuke Tsutsumi, Takao Ohtsuka, Shunichi Takahata, Masao Tanaka, Hidechika Okada

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)452-460
Number of pages9
JournalJournal of gastroenterology
Volume47
Issue number4
DOIs
Publication statusPublished - Apr 2012

All Science Journal Classification (ASJC) codes

  • Gastroenterology

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