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Downregulation of CDC20 Increases Radiosensitivity through Mcl-1/p-Chk1-Mediated DNA Damage and Apoptosis in Tumor Cells

文献类型：期刊论文

作者Gao, Yang1,2,3; Wen, Pengbo4; Chen, Bin1,2,3; Hu, Guanshuo1,2,3; Wu, Lijun1,2; Xu, An1,2; Zhao, Guoping1,2
刊名INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
出版日期2020-09-01
卷号21
关键词CDC20 radiotherapy Mcl-1 p-Chk1 mitochondrial-dependent apoptotic pathway
DOI10.3390/ijms21186692
通讯作者Zhao, Guoping(gpz@ipp.ac.cn)
英文摘要Radiotherapy is an important modality for the local control of human cancers, but the radioresistance induced by aberrant apoptotic signaling is a hallmark of cancers. Restoring the aberrant apoptotic pathways is an emerging strategy for cancer radiotherapy. In this study, we determined that targeting cell division cycle 20 (CDC20) radiosensitized colorectal cancer (CRC) cells through mitochondrial-dependent apoptotic signaling. CDC20 was overexpressed in CRC cells and upregulated after radiation. Inhibiting CDC20 activities genetically or pharmacologically suppressed the proliferation and increased radiation-induced DNA damage and intrinsic apoptosis in CRC cells. Mechanistically, knockdown of CDC20 suppressed the expression of antiapoptotic protein Mcl-1 but not other Bcl-2 family proteins. The expressions of CDC20 and Mcl-1 respond to radiation simultaneously through direct interaction, as evidenced by immunoprecipitation and glutathione S-transferase (GST) pull-down assays. Subsequently, decreased Mcl-1 expression inhibited the expression level of phosphorylated checkpoint kinase 1 (p-Chk1), thereby resulting in impaired DNA damage repair through downregulating the homologous recombination repair protein Rad51 and finally causing apoptotic signaling. In addition, both CDC20 and Chk1 inhibitors together, through in vivo studies, confirmed the radiosensitizing effect of CDC20 via inhibiting Mcl-1 and p-Chk1 expression. In summary, our results indicate that targeting CDC20 is a promising strategy to improve cancer radiotherapy.
WOS关键词CANCER THERAPEUTIC TARGET ; MITOTIC EXIT ; MOLECULAR-MECHANISMS ; MCL-1 ; CHECKPOINT ; CHK1 ; INHIBITOR ; CYCLE ; ABROGATION ; AZD7762
资助项目National Natural Science Foundation of China[11835014] ; National Natural Science Foundation of China[31870845] ; CAS Pioneer Hundred Talents Program ; National Natural Science Foundation of China
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
WOS记录号WOS:000581262800001
出版者MDPI
资助机构National Natural Science Foundation of China ; CAS Pioneer Hundred Talents Program ; National Natural Science Foundation of China
源URL[http://ir.hfcas.ac.cn:8080/handle/334002/104609]  
专题中国科学院合肥物质科学研究院
通讯作者Zhao, Guoping
作者单位1.Chinese Acad Sci, Hefei Inst Phys Sci, Key Lab High Magnet Field & Ion Beam Phys Biol, Hefei 230031, Peoples R China
2.Anhui Prov Key Lab Environm Toxicol & Pollut Cont, Hefei 230031, Peoples R China
3.Univ Sci & Technol China, Sch Grad Students, Hefei 230026, Peoples R China
4.Xuzhou Med Univ, Sch Med Informat, Dept Bioinformat, Xuzhou 221004, Jiangsu, Peoples R China
推荐引用方式
GB/T 7714		 Gao, Yang,Wen, Pengbo,Chen, Bin,et al. Downregulation of CDC20 Increases Radiosensitivity through Mcl-1/p-Chk1-Mediated DNA Damage and Apoptosis in Tumor Cells[J]. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,2020,21.
APA Gao, Yang.,Wen, Pengbo.,Chen, Bin.,Hu, Guanshuo.,Wu, Lijun.,...&Zhao, Guoping.(2020).Downregulation of CDC20 Increases Radiosensitivity through Mcl-1/p-Chk1-Mediated DNA Damage and Apoptosis in Tumor Cells.INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,21.
MLA Gao, Yang,et al."Downregulation of CDC20 Increases Radiosensitivity through Mcl-1/p-Chk1-Mediated DNA Damage and Apoptosis in Tumor Cells".INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 21(2020).

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来源：合肥物质科学研究院

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