Comprehensive multi-omics analysis elucidates colchicine-induced toxicity mechanisms and unveils the therapeutic potential of MLN4924 and kinase inhibitors
文献类型：期刊论文
| 作者 | Zhai, Lin-hui6,7; Jia, Xing-long4,5; Chen, Yu-lu7; Liu, Mu-yin3,5; Zhang, Jing-dan1,2; Ma, Shao-jie7; Wang, Xiu-jun7; Cheng, Wen-hao7; He, Jing-liang7; Zhou, Jiao-jiao7 |
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2024-11-20 |
| 页码 | 13 |
| 关键词 | colchicine MLN4924 multi-omics analysis phosphoproteomics ubiquitinomics kinase inhibitor |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/s41401-024-01422-5 |
| 通讯作者 | Tan, Min-jia(mjtan@simm.ac.cn) ; Liu, Bin(liubin@jou.edu.cn) |
| 英文摘要 | Colchicine is a widely prescribed anti-inflammatory drug for the treatment of gout, familial Mediterranean fever and pericarditis, but its narrow therapeutic window presents a significant risk of severe toxicity. Despite its clinical relevance, the molecular mechanisms underlying colchicine's pharmacological effects and associated toxicity and explored potential therapeutic interventions to mitigate its adverse effects. We showed the colchicine's impact on cellular morphology in human umbilical vein endothelial cells (HUVEC) and HeLa cells including cell rounding and detachment following 24 h of exposure that revealed pronounced cytotoxic effects. We then established a large-scale screening model to identify small molecules capable of reversing colchicine-induced cellular toxicity, and identified MLN4924, an inhibitor of the Cullin-RING E3 ligase (CRL) system, as a promising candidate for mitigating colchicine-induced cellular injury. Through a comprehensive multi-omics approach including transcriptomics, proteomics, phosphoproteomics and ubiquitinomics, we systematically characterized the molecular perturbations caused by colchicine and delineated the protective mechanisms of MLN4924. We found that MLN4924 exerted its protective effects by modulating critical cellular pathways, specifically preventing the dysregulation of cell cycle progression, mitotic disruption and microtubule destabilization triggered by colchicine. Furthermore, proteomic and phosphoproteomic analyses revealed significant alterations in kinase signaling networks, with combined inhibition of CDK1 and PAK1 emerging as an effective strategy to counteract colchicine-induced cellular dysfunction. These results not only provide a detailed molecular characterization of colchicine toxicity but also identify key therapeutic targets, laying the groundwork for the development of targeted interventions to mitigate colchicine-induced adverse effects in clinical practice. |
| WOS关键词 | NEDD8-ACTIVATING ENZYME ; EXPRESSION ; CANCER |
| 资助项目 | National Natural Science Foundation of China[82273167] ; National Natural Science Foundation of China[22225702] ; National Natural Science Foundation of China[32171434] ; Program of Shanghai Academic Research Leader[22XD1420900] ; State Key Laboratory of Drug Research[SIMM2105KF-13] ; Jiangsu Province Basic Research Program Natural Science Foundation (Outstanding Youth Fund Project)[BK20220063] ; Key Program of Basic Science (Natural Science) of Jiangsu Province[22KJA350001] ; Huaguo Mountain Talent Plan of Lianyungang City (Innovative Talents) |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001359314700001 |
| 出版者 | NATURE PUBL GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/314583]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Tan, Min-jia; Liu, Bin |
| 作者单位 | 1.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China 2.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou 510515, Peoples R China 3.Fudan Univ, Zhongshan Hosp, Shanghai Inst Cardiovasc Dis, Dept Cardiol, Shanghai, Peoples R China 4.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 6.Tongji Univ, Shanghai Peoples Hosp 4, Translat Res Inst Brain & Brain Like Intelligence, Sch Med, Shanghai, Peoples R China 7.Jiangsu Ocean Univ, Coll Pharm, Jiangsu Key Lab Marine Pharmaceut Cpd Screening, Lianyungang 222005, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhai, Lin-hui,Jia, Xing-long,Chen, Yu-lu,et al. Comprehensive multi-omics analysis elucidates colchicine-induced toxicity mechanisms and unveils the therapeutic potential of MLN4924 and kinase inhibitors[J]. ACTA PHARMACOLOGICA SINICA,2024:13. |
| APA | Zhai, Lin-hui.,Jia, Xing-long.,Chen, Yu-lu.,Liu, Mu-yin.,Zhang, Jing-dan.,...&Liu, Bin.(2024).Comprehensive multi-omics analysis elucidates colchicine-induced toxicity mechanisms and unveils the therapeutic potential of MLN4924 and kinase inhibitors.ACTA PHARMACOLOGICA SINICA,13. |
| MLA | Zhai, Lin-hui,et al."Comprehensive multi-omics analysis elucidates colchicine-induced toxicity mechanisms and unveils the therapeutic potential of MLN4924 and kinase inhibitors".ACTA PHARMACOLOGICA SINICA (2024):13. |
入库方式： OAI收割
来源：上海药物研究所
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