Institute of Chinese Materia Medica and Artemisinin Research Center, Academy of Chinese Medical Sciences, Beijing 100700, China.
Department of physiology, School of Basic Medical Sciences, Guangxi Medical University, Nanning 530022, China; Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning 530022, China.
Phytomedicine. 2022 Jul;101:154096. doi: 10.1016/j.phymed.2022.154096. Epub 2022 Apr 11.
Celastrol (Cel) is a naturally-derived compound with anti-cancer properties and exerts beneficial effects against various diseases. Although an extensive body of research already exists for Cel, the vast majority are inductive studies with limited validation of specific pathways and functions. The cellular targets that bind to Cel remain poorly characterized, which limits attempts to uncover its mechanism of action.
The present study aims to comprehensively identify the protein targets of Cel in HCT116 cells in an unbiased manner, and elucidate the mechanism of the anti-cancer activity of Cel based on target information.
A comprehensive analysis of protein targets that bind to Cel was performed in HCT116 colon cancer cells using a quantitative chemical biology method. A Cel probe (Cel-P) was synthesized to allow in situ monitoring of treatment in living HCT116 cells, and specific targets were identified with a quantitative chemical biology method (isobaric tags for relative and absolute quantitation) using mass spectrometry.
In total, 100 protein targets were identified as specific targets of Cel. Pathways associated with the targets were investigated. Multiple pathways were demonstrated to be potential effectors of Cel. These pathways included the suppression of protein synthesis, deregulation of cellular reactive oxygen species, and suppression of fatty acid metabolism, and they were validated with in vitro experiments.
The extensive information on the protein targets of Cel and their functions uncovered by this study will enhance the current understanding of the mechanism of action of Cel and serve as a valuable knowledge base for future studies.
雷公藤红素（Cel）是一种具有抗癌特性的天然衍生化合物，对多种疾病有有益的作用。尽管已经有大量的 Cel 相关研究，但绝大多数都是具有局限性的诱导性研究，对特定途径和功能的验证有限。与 Cel 结合的细胞靶标仍未得到很好的描述，这限制了对其作用机制的探索。
本研究旨在以无偏倚的方式全面鉴定 Cel 在 HCT116 细胞中的蛋白靶标，并基于靶标信息阐明 Cel 的抗癌活性机制。
采用定量化学生物学方法，在结肠癌细胞 HCT116 中全面分析与 Cel 结合的蛋白靶标。合成 Cel 探针（Cel-P），以允许在活 HCT116 细胞中进行原位监测治疗，并使用质谱的定量化学生物学方法（相对和绝对定量的同重同位素标记）鉴定特定的靶标。
共鉴定出 100 个 Cel 的特异性靶标。研究了与这些靶标相关的途径。证明了多个途径可能是 Cel 的效应器。这些途径包括抑制蛋白质合成、细胞活性氧物质失调和抑制脂肪酸代谢，并用体外实验进行了验证。
本研究揭示了 Cel 的广泛蛋白靶标及其功能信息，将增强对 Cel 作用机制的理解，并为未来的研究提供有价值的知识库。
