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 language | English |
|---|---|
| Pages (from-to) | 452-460 |
| Number of pages | 9 |
| Journal | Journal of Gastroenterology |
| Volume | 47 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Apr 2012 |
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All Science Journal Classification (ASJC) codes
- Gastroenterology
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Targeting the hedgehog signaling pathway with interacting peptides to Patched-1. / Nakamura, Masafumi; Tanaka, Haruo; Nagayoshi, Yousuke; Nakashima, Hiroshi; Tsutsumi, Kosuke; Takao, Ohtsuka; Takahata, Shunichi; Tanaka, Masao; Okada, Hidechika.
In: Journal of Gastroenterology, Vol. 47, No. 4, 04.2012, p. 452-460.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Targeting the hedgehog signaling pathway with interacting peptides to Patched-1
AU - Nakamura, Masafumi
AU - Tanaka, Haruo
AU - Nagayoshi, Yousuke
AU - Nakashima, Hiroshi
AU - Tsutsumi, Kosuke
AU - Takao, Ohtsuka
AU - Takahata, Shunichi
AU - Tanaka, Masao
AU - Okada, Hidechika
PY - 2012/4
Y1 - 2012/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84863087715&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84863087715&partnerID=8YFLogxK
U2 - 10.1007/s00535-011-0507-6
DO - 10.1007/s00535-011-0507-6
M3 - Article
C2 - 22170414
AN - SCOPUS:84863087715
VL - 47
SP - 452
EP - 460
JO - Journal of Gastroenterology
JF - Journal of Gastroenterology
SN - 0944-1174
IS - 4
ER -