Aptamer Inhibits Tumor Growth by Leveraging Cellular Proteasomal Degradation System to Degrade c-Met in Mice

被引：85

作者：

Chen, Kun ^{[1
]}

Cai, Jiamin ^{[1
]}

Wang, Sujuan ^{[1
]}

Li, Yingying ^{[1
]}

Yang, Chan ^{[1
]}

Fu, Ting ^{[1
]}

Zhao, Zilong ^{[1
]}

Zhang, Xiaobing ^{[1
]}

Tan, Weihong ^{[1
,2
,3
,4
]}

机构：

[1] Hunan Univ, Coll Chem & Chem Engn, Aptamer Engn Ctr Hunan Prov, Mol Sci & Biomed Lab MBL,State Key Lab Chemo Biose, Changsha 410082, Hunan, Peoples R China

[2] Zhejiang Canc Hosp, Hangzhou Inst Med HIM, Chinese Acad Sci, Hangzhou 310022, Zhejiang, Peoples R China

[3] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Inst Mol Med IMM, Shanghai 200240, Peoples R China

[4] Shanghai Jiao Tong Univ, Coll Chem & Chem Engn, Shanghai 200240, Peoples R China

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2023年 / 62卷 / 02期

基金：

国家重点研发计划; 中国国家自然科学基金;

关键词：

Aptamer; Cancer Therapy; c-Met; Proteasomal Degradation System; Protein Degradation; DNA APTAMER; CANCER; NUCLEOLIN; TARGET; DOMAIN; AS1411; CELLS;

D O I：

10.1002/anie.202208451

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Current action mechanisms for aptamer-based therapeutics depend on occupancy-driven pharmacology to mediate protein functions. We report a new mechanism where aptamers leverage cellular proteasomal degradation system to degrade proteins for cancer treatment. A DNA aptamer (hereinafter referred to as c-Met-Ap) binds to the extracellular domain of mesenchymal-epithelial transition factor (c-Met) and selectively induces c-Met phosphorylation at Y1003 and Y1349. The phosphorylation of Y1003 recruits E3 ubiquitin ligase casitas B-lineage lymphoma, causing c-Met ubiquitination and degradation in the proteasome. Furthermore, c-Met-Ap can induce a decrease in the heterodimeric partner proteins of c-Met and the downstream effector proteins in the c-Met signal axis, effectively inhibiting tumor growth in A549 tumor-bearing BALB/c mice. Our study uncovers a novel, actionable mechanism for aptamer therapeutics and opens a new avenue for developing highly efficient anticancer drugs.

引用

页数：8

共 43 条

[1] What is the right dose? The elusive optimal biologic dose in phase I clinical trials [J].