S100P-derived RAGE antagonistic peptide reduces tumor growth and metastasis.
S100P-derived RAGE antagonistic peptide reduces tumor growth and metastasis.
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DOI：
10.1158/1078-0432.ccr-12-0221
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发表时间：
2012-08-15
期刊：
影响因子：
--
通讯作者：
Logsdon CD
中科院分区：
文献类型：
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作者：
Arumugam T;Ramachandran V;Gomez SB;Schmidt AM;Logsdon CD
晚期糖基化终末产物受体（AGEs）导致多种病理，包括糖尿病、关节炎、神经退行性疾病和癌症。尽管有明显的需求，但临床上并没有常用的β-内酰胺酶抑制剂。因此，我们开发了一种新的小分子β受体拮抗剂肽（RAP），它可以阻断多种配体的激活。通过对人胰腺组织的免疫组织化学分析来观察人胰腺癌及其配体，并使用siRNA来分析它们的功能。ELISA法测定了S100 P、S100 A4和HMGB-1与β-内酰胺酶的相互作用。设计、合成了三种S100 P衍生的小拮抗肽，并测试了其对β-内酰胺酶结合的抑制作用。使用肽阻断剂对NFκ B-荧光素酶报告基因活性的影响来评估对NFκ B介导的信号传导的影响。在神经胶质瘤和胰腺导管腺癌（PDAC）模型上测试最有效的肽。免疫组织化学分析证实PDAC中有HMGB-I及其配体S100 P、S100 A4和HMGB-I的表达。siRNA沉默PDAC或其配体在体外降低PDAC细胞的生长和迁移。在微摩尔浓度下，最有效的β-内酰胺酶拮抗肽（RAP）抑制S100 P、S100 A4和HMGB-1与β-内酰胺酶的相互作用。RAP还在体外和体内降低了配体刺激癌细胞中NFκB活化的能力。重要的是，RAP的全身体内施用减少胰腺肿瘤的生长和转移，并且还抑制神经胶质瘤肿瘤的生长。RAP显示出作为研究RAGE功能的工具和作为RAGE相关疾病的体内治疗的前景。
The receptor for advanced glycation end products (RAGE) contributes to multiple pathologies, including diabetes, arthritis, neurodegenerative diseases, and cancer. Despite the obvious need, no RAGE inhibitors are in common clinical use. Therefore, we developed a novel small RAGE antagonist peptide (RAP) which blocks activation by multiple ligands. RAGE and its ligands were visualized by immunohistochemical analysis of human pancreatic tissues, and siRNA was used to analyze their functions. Interactions between RAGE and S100P, S100A4, and HMGB-1 were measured by ELISA. Three S100P-derived small antagonistic peptides were designed, synthesized, and tested for inhibition of RAGE binding. The effects of the peptide blockers on NFκB-luciferase reporter activity was used to assess effects on RAGE mediated signaling. The most effective peptide was tested on glioma and pancreatic ductal adenocarcinoma (PDAC) models. Immunohistochemical analysis confirmed the expression of RAGE and its ligands S100P, S100A4, and HMGB-1 in human PDAC. siRNA silencing of RAGE or its ligands reduced the growth and migration of PDAC cells in vitro. The most effective RAGE antagonistic peptide (RAP) inhibited the interaction of S100P, S100A4, and HMGB-1 with RAGE at micromolar concentrations. RAP also reduced the ability of the ligands to stimulate RAGE activation of NFκB in cancer cells in vitro and in vivo. Importantly, systemic in vivo administration of RAP reduced the growth and metastasis of pancreatic tumors and also inhibited glioma tumor growth. RAP shows promise as a tool for the investigation of RAGE function and as an in vivo treatment for RAGE-related disorders.