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Aptamer Inhibits Tumor Growth by Leveraging Cellular Proteasomal Degradation System to Degrade c‐Met in Mice
- Source :
- Angewandte Chemie International Edition. 62
- Publication Year :
- 2022
- Publisher :
- Wiley, 2022.
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Abstract
- 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.
- Subjects :
- General Medicine
General Chemistry
Catalysis
Subjects
Details
- ISSN :
- 15213773 and 14337851
- Volume :
- 62
- Database :
- OpenAIRE
- Journal :
- Angewandte Chemie International Edition
- Accession number :
- edsair.doi.dedup.....62b475a9dc4e2700f65a2a234e98ecb8