Related Experiment Video
Updated: Aug 6, 2025
Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions
Published on: December 1, 2020
Chemoproteomics Reveals That Quaternary Protoberberine Alkaloids Inhibit Telomerase Activity Oncologically by Binding
Ling-Wen Xu1, Xue-Qian Zhang1, Zheng Yan1
1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
Abstract:
Natural QPAs have anti-cancer property. The prodrugs of QPAs synthesized in our work with significantly improved solubility showed significantly stronger activity in animal experiments. Nevertheless, the mechanism of action of QPAs for treating cancers remains poorly understood. Here, a chemoproteomic study reveals that QPAs non-covalently and multivalently bind to PES1 in CRC cells, which impinges on the direct interaction between hTERT and hTR in the assembly of the telomerase complex, downregulates telomerase activity, and so promotes the aging process of CRC cells. This study is beneficial for us to conduct extensively the pharmaceutical chemistry research of QPAs.
Insights
Quassinoids (QPAs) show anti-cancer effects by targeting PES1 in colorectal cancer (CRC) cells. This binding disrupts telomerase assembly, reducing its activity and promoting cancer cell aging.
Area of Science:
- Pharmacology
- Molecular Biology
- Oncology
Background:
- Natural quassinoids (QPAs) possess anti-cancer properties.
- Synthesized QPA prodrugs exhibit enhanced solubility and efficacy in preclinical models.
- The precise mechanism of QPA anti-cancer action is not fully elucidated.
Purpose of the Study:
- To investigate the molecular mechanism of Quassinoids (QPAs) in colorectal cancer (CRC).
- To identify the direct molecular target of QPAs in cancer cells.
- To understand how QPAs affect telomerase activity and cancer cell fate.
Main Methods:
- Chemoproteomic profiling to identify QPA-binding proteins.
- In vitro assays to assess protein-protein interactions and enzyme activity.
- Cellular assays to evaluate telomerase function and cell aging in CRC cells.
Main Results:
- QPAs bind non-covalently and multivalently to PES1 within CRC cells.
- QPA binding to PES1 inhibits the interaction between hTERT and hTR.
- This leads to downregulation of telomerase activity and induction of CRC cell senescence.
Conclusions:
- QPAs exert anti-cancer effects by targeting PES1 and inhibiting telomerase complex formation.
- The identified mechanism provides a basis for further pharmaceutical chemistry research on QPAs.
- This study elucidates a novel pathway for QPA-mediated cancer therapy.
