Targeting the hedgehog signaling pathway with interacting peptides to Patched-1
Targeting the hedgehog signaling pathway with interacting peptides to Patched-1
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DOI：
10.1007/s00535-011-0507-6
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发表时间：
2012-04-01
影响因子：
6.3
通讯作者：
Okada, Hidechika
中科院分区：
文献类型：
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作者：
Nakamura, Masafumi;Tanaka, Haruo;Okada, Hidechika
在许多癌症中，hedgehog (Hh) 信号通路被异常激活。 Hh 通路中的配体 sonic hedgehog (Shh) 的过量产生通过抑制 Hh 通路中的抑制性受体 Patched-1 (Ptch1) 来增加 Hh 信号传导活性。本研究的目的是通过控制 Ptch1 的肿瘤抑制功能来建立治疗胰腺癌和其他 Hh 依赖性癌症的新策略。我们合成了 7 个与 Shh 的 Ptch1 对接位点氨基酸序列相互作用的肽。在存在或不存在肽的情况下培养人胰腺癌细胞系（AsPC-1、SUIT2）。通过细胞计数和3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑(MTT)测定评估细胞增殖。 Hh途径的活性通过目标基因产物Gli1的实时聚合酶链反应来估计。为了证实它们的体内抗肿瘤活性，确定了这些肽在小鼠胰腺癌模型中的作用。最后，检查了异种移植物的 Hh 信号活性。在体外和体内，三种 Ptch1 相互作用肽抑制了两种胰腺癌细胞系的增殖，并降低了 Gli1 的表达。这项研究表明，Ptch1 相互作用肽可能是控制胰腺癌 Hh 依赖性生长的新工具。
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.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.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.This study suggests that interacting peptides to Ptch1 may be a new tool for controlling the Hh-dependent growth of pancreatic cancer.