Norcantharidin promotes cancer radiosensitization through Cullin1 neddylation-mediated CDC6 protein degradation

作者全名："Deng, Tanggang; Zhu, Qianling; Xie, Lin; Liu, Youhong; Peng, Yuchong; Yin, Linglong; Gao, Yingxue; Cao, Tuoyu; Fu, Yuxin; Qi, Xuli; Zhang, Songwei; Peng, Yongbo; Hou, Youxiang; Li, Xiong"

作者地址："[Deng, Tanggang; Xie, Lin; Peng, Yuchong; Yin, Linglong; Li, Xiong] Guangdong Pharmaceut Univ, Affiliated Hosp 1, Dept Clin Pharm, 19 Nonglinxia Rd, Guangzhou, Guangdong, Peoples R China; [Deng, Tanggang; Xie, Lin; Peng, Yuchong; Yin, Linglong; Li, Xiong] Guangdong Pharmaceut Univ, Affiliated Hosp 1, Ctr Clin Precis Pharm, Guangzhou, Guangdong, Peoples R China; [Zhu, Qianling; Liu, Youhong; Gao, Yingxue; Cao, Tuoyu; Fu, Yuxin; Qi, Xuli; Zhang, Songwei] Cent South Univ, Xiangya Hosp, Dept Oncol, Ctr Mol Med, Changsha, Hunan, Peoples R China; [Zhu, Qianling; Liu, Youhong; Gao, Yingxue; Cao, Tuoyu; Fu, Yuxin; Qi, Xuli; Zhang, Songwei] Xiangya Hosp, Cent South Univ, Hunan Key Lab Mol Radiat Oncol, Changsha, Hunan, Peoples R China; [Yin, Linglong] Guangdong Pharmaceut Univ, Sch Clin Pharm, Guangzhou, Guangdong, Peoples R China; [Peng, Yongbo] Chongqing Med Univ, Sch Pharm, Chongqing, Peoples R China; [Hou, Youxiang] Xinjiang Med Univ, Tumor Hosp, Dept Radiat Oncol, Xinjiang, Peoples R China; [Li, Xiong] Guangdong Pharmaceut Univ, NMPA Key Lab Technol Res & Evaluat Pharmacovigil, Guangzhou, Guangdong, Peoples R China"

通信作者："Li, X (通讯作者)，Guangdong Pharmaceut Univ, Affiliated Hosp 1, Dept Clin Pharm, 19 Nonglinxia Rd, Guangzhou, Guangdong, Peoples R China."

来源：MOLECULAR CARCINOGENESIS

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000804782400001

JCR分区：Q2

影响因子：4.6

年份：2022

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：CDC6; Norcantharidin; protein degradation; ubiquitin-proteasome pathway

摘要："Radiotherapy (RT) is a conventional cancer therapeutic modality. However, cancer cells tend to develop radioresistance after a period of treatment. Diagnostic markers and therapeutic targets for radiosensitivity are severely lacking. Our recently published studies demonstrated that the cell division cycle (CDC6) is a critical molecule contributing to radioresistance, and maybe a potential therapeutic target to overcome radioresistance. In the present study, we for the first time reported that Norcantharidin (NCTD), a demethylated form of cantharidin, re-sensitized radioresistant cancer cells to overcome radioresistance, and synergistically promoted irradiation (IR)-induced cell killing and apoptosis by inducing CDC6 protein degradation. Mechanistically, NCTD induced CDC6 protein degradation through the ubiquitin-proteasome pathways. By using small interfering RNA (siRNA) interference or small compound inhibitors, we further determined that NCTD induced CDC6 protein degradation through a neddylation-dependent pathway, but not through Huwe1, Cyclin F, and APC/C-mediated ubiquitin-proteasome pathways. We screened the six most relevant Cullin subunits (CUL1, 2, 3, 4A, 4B, and 5) using siRNAs. The knockdown of Cullin1 but not the other five cullins remarkably elevated CDC6 protein levels. NCTD promoted the binding of Cullin1 to CDC6, thereby promoting CDC6 protein degradation through a Cullin1 neddylation-mediated ubiquitin-proteasome pathway. NCTD can be used in combination with radiotherapy to achieve better anticancer efficacy, or work as a radiosensitizer to overcome cancer radioresistance."

基金机构："National Key Discipline Construction Project, High Level Clinical Key Discipline in Guangdong Province; Guangzhou Science and Technology Plan Projects; Research Project of Key Discipline of Guangdong Province; Guangdong Basic and Applied Basic Research Foundation; National Natural Science Foundation of China"

基金资助正文："National Key Discipline Construction Project, High Level Clinical Key Discipline in Guangdong Province; Guangzhou Science and Technology Plan Projects; Research Project of Key Discipline of Guangdong Province; Guangdong Basic and Applied Basic Research Foundation; National Natural Science Foundation of China"