Norcantharidin promotes cancer radiosensitization through Cullin1 neddylation‐mediated CDC6 protein degradation
Norcantharidin promotes cancer radiosensitization through Cullin1 neddylation‐mediated CDC6 protein degradation
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去甲斑蝥素通过 Cullin1 neddylation 介导的 CDC6 蛋白降解促进癌症放射增敏
DOI：
10.1002/mc.23435
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发表时间：
2022-06
期刊：
影响因子：
--
通讯作者：
Xiong Li
中科院分区：
文献类型：
--
作者：
Tanggang Deng;Qianling Zhu;Lin Xie;Youhong Liu;Yuchong Peng;Linglong Yin;Yingxue Gao;Tuoyu Cao;Yuxin Fu;Xuli Qi;Songwei Zhang;Yongbo Peng;Youxiang Hou;Xiong Li
放射治疗（RT）是一种常规的癌症治疗方式。然而，癌细胞在治疗一段时间后往往会产生放射抗性。放射敏感性的诊断标志物和治疗靶点严重缺乏。我们最近发表的研究表明，细胞分裂周期（CDC 6）是一个关键的分子有助于辐射抗性，并可能是一个潜在的治疗目标，以克服辐射抗性。在本研究中，我们首次报道了去甲基化藜芦醇苷（NCTD），去甲基化藜芦醇苷的形式，重新敏化辐射抗性癌细胞，克服辐射抗性，并协同促进辐射（IR）诱导的细胞杀伤和凋亡诱导的CDC 6蛋白降解。NCTD通过泛素-蛋白酶体途径诱导CDC 6蛋白降解。通过使用小干扰RNA（siRNA）干扰或小化合物抑制剂，我们进一步确定NCTD通过neddylation依赖性途径诱导CDC 6蛋白降解，而不是通过Huwe 1、Cyclin F和APC/C介导的泛素-蛋白酶体途径。我们使用siRNA筛选了六个最相关的Cullin亚基（CUL 1、2、3、4A、4 B和5）。Cullin 1的敲除而不是其他五个cullin显著提高了CDC 6蛋白水平。NCTD促进Cullin 1与CDC 6的结合，从而通过Cullin 1 neddylation介导的泛素-蛋白酶体途径促进CDC 6蛋白的降解。NCTD可与放射治疗联合使用以获得更好的抗癌疗效，或作为放射增敏剂以克服癌症的放射抗性。
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.
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DOI：
10.1083/jcb.201211019
发表时间：
2013-06-24
期刊：
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影响因子：
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DOI：
10.1186/s13046-018-0758-7
发表时间：
2018-04-23
期刊：
Journal of experimental & clinical cancer research : CR
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作者：
Tang L;Wei F;Wu Y;He Y;Shi L;Xiong F;Gong Z;Guo C;Li X;Deng H;Cao K;Zhou M;Xiang B;Li X;Li Y;Li G;Xiong W;Zeng Z
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