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Pharmacological targeting of Axin2 suppresses cell growth and metastasis in colorectal cancer

文献类型：期刊论文

作者Cheng, Li-Zhi1; Huang, Dan-Ling2; Tang, Zhang-Rui1; Zhang, Jia-Hao1; Xiong, Ting1; Zhou, Chen3; Zhang, Nai-Xia3; Fu, Rong1; Cheng, Yong-Xian2; Wu, Zhao-Qiu1
刊名BRITISH JOURNAL OF PHARMACOLOGY
出版日期2023-08-18
页码21
ISSN号0007-1188
关键词colorectal cancer progression GSK3 beta-Axin2 interaction small-molecule inhibitor Snail beta-Trcp2
DOI10.1111/bph.16193
通讯作者Fu, Rong(furong@cpu.edu.cn) ; Cheng, Yong-Xian(yxcheng@szu.edu.cn) ; Wu, Zhao-Qiu(zqwu@cpu.edu.cn)
英文摘要Background and Purpose: The scaffold molecule Axin2 is constitutively activated in colorectal cancer (CRC) and functions as a potent promoter of CRC behaviour. Pharmacological targeting of Axin2 may therefore exert a therapeutic effect in patients with CRC. Here, we discovered a potent small-molecule inhibitor of Axin2, based on the mechanism by which Axin2 is regulated post-translationally, and investigated its antitumour effects. Experimental Approach: Compound discovery and its inhibitory action on Axin2 protein were revealed by microscale thermophoresis, in vitro kinase assay, quantitative kinetic assay, immunoblotting/immunoprecipitation, RT-qPCR and cycloheximide pulse-chase assay. Compound antitumour effects and the underlying mechanisms were evaluated in multiple cell-based assays and mouse models. Key Results: We discovered that glycogen synthase kinase 3 beta (GSK3 beta) phosphorylates Axin2 at two consensus motifs and coupled Axin2 phosphorylation to its ubiquitination (mediated by the E3 ligase beta-Trcp2) and proteasomal degradation. The binding of Axin2 to GSK3 beta in CRC cells is faint, which enables most of the Axin2 protein to maintain an unphosphorylated status and thereby permits the cells to preserve high levels of Axin2. Importantly, we identified a small-molecule compound CW85319 that enhances Axin2's interaction with GSK3 beta via forming a high affinity for Axin2. Treatment of CRC cells with CW85319 enhanced Axin2 binding with GSK3 beta, thereby promoting Axin2 phosphorylation, subsequent ubiquitination, and degradation. Furthermore, we demonstrated that CW85319 efficiently suppressed Axin2-driven CRC growth and metastasis, without eliciting side toxicity. Conclusions and Implications: These findings suggest that pharmacological targeting of Axin2 by CW85319 may provide therapeutic benefits against certain human cancers, especially CRC.
WOS关键词BETA-CATENIN ; CHROMOSOMAL INSTABILITY ; KAPPA-B ; WNT ; KINASE ; PHOSPHORYLATION ; DESTRUCTION ; PROGRESSION ; EXPRESSION ; BETA-TRCP1
资助项目National Natural Science Foundation of China[81973363] ; National Natural Science Foundation of China[82125036] ; National Natural Science Foundation of China[82273964] ; State Key Laboratory of Natural Medicines of CPU[SKLNMZZ202207] ; Double-First Class' Program of CPU[CPU2022QZ22] ; National Key Research and Development Program of China[2017YFA0503900] ; Shenzhen Fundamental Research Program[JCYJ20200109114225087] ; Shenzhen Science and Technology Program[KQTD20210811090219022]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者WILEY
WOS记录号WOS:001051032000001
源URL[http://119.78.100.183/handle/2S10ELR8/306962]  
专题新药研究国家重点实验室
通讯作者Fu, Rong; Cheng, Yong-Xian; Wu, Zhao-Qiu
作者单位1.China Pharmaceut Univ, Sch Pharm, Dept Pharmacol, State Key Lab Nat Med, Nanjing 211198, Peoples R China
2.Shenzhen Univ Hlth Sci Ctr, Inst Inheritance Based Innovat Chinese Med, Sch Pharmaceut Sci, Shenzhen 518060, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Cheng, Li-Zhi,Huang, Dan-Ling,Tang, Zhang-Rui,et al. Pharmacological targeting of Axin2 suppresses cell growth and metastasis in colorectal cancer[J]. BRITISH JOURNAL OF PHARMACOLOGY,2023:21.
APA Cheng, Li-Zhi.,Huang, Dan-Ling.,Tang, Zhang-Rui.,Zhang, Jia-Hao.,Xiong, Ting.,...&Wu, Zhao-Qiu.(2023).Pharmacological targeting of Axin2 suppresses cell growth and metastasis in colorectal cancer.BRITISH JOURNAL OF PHARMACOLOGY,21.
MLA Cheng, Li-Zhi,et al."Pharmacological targeting of Axin2 suppresses cell growth and metastasis in colorectal cancer".BRITISH JOURNAL OF PHARMACOLOGY (2023):21.

入库方式： OAI收割

来源：上海药物研究所

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