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

被引:13
作者
Gao, Yang [1 ,2 ,3 ]
Wen, Pengbo [4 ]
Chen, Bin [1 ,2 ,3 ]
Hu, Guanshuo [1 ,2 ,3 ]
Wu, Lijun [1 ,2 ]
Xu, An [1 ,2 ]
Zhao, Guoping [1 ,2 ]
机构
[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
基金
中国国家自然科学基金;
关键词
CDC20; radiotherapy; Mcl-1; p-Chk1; mitochondrial-dependent apoptotic pathway; CANCER THERAPEUTIC TARGET; MITOTIC EXIT; MOLECULAR-MECHANISMS; MCL-1; CHECKPOINT; CHK1; INHIBITOR; CYCLE; ABROGATION; AZD7762;
D O I
10.3390/ijms21186692
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
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.
引用
收藏
页码:1 / 18
页数:18
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