DNA损伤诱导的KIFC1磷酸化介导肿瘤耐药和复发的机制及策略研究
结题报告
批准号:
31970720
项目类别:
面上项目
资助金额:
58.0 万元
负责人:
范广建
依托单位:
学科分类:
细胞信号转导
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
范广建
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中文摘要
中心体过度复制的细胞存在于各类肿瘤中,该类细胞面临两种命运:通过Centrosome Clustering-凝集多余中心体得以生存,并促进基因组不稳定性,增加肿瘤耐药、复发概率;未凝集多余中心体的细胞则走向死亡。因此抑制多余中心体凝集成为肿瘤治疗的曙光方向,但机制仍待研究。我们首次发现放化疗通过DNA损伤促进多余中心体凝集,导致本应死亡的肿瘤细胞生存下来。机制上在DNA损伤应激下,驱动蛋白KIFC1发生ATM/ATR依赖的Ser26磷酸化(质谱、抑制剂与免疫共沉淀实验确证)并增强其蛋白稳定性从而促进中心体凝集,导致基因组不稳定性、肿瘤耐药和复发;临床上初步证实KIFC1与肿瘤恶化、复发相关。因此在肿瘤放化疗中,如选择合适药物抑制KIFC1磷酸化介导的多余中心体凝集可减少耐药和复发概率。综上,我们拟研究KIFC1-S26磷酸化在肿瘤耐药和复发中的关键作用,为肿瘤检验与治疗提供新靶点、新策略。
英文摘要
Centrosome amplification (CA) is a hallmark of cancers and induced by radiotherapy and chemotherapy drugs. Only through clustering extra centrosomes (Centrosome Clustering) can tumor cells survive and be accompanied by genomic instability which provides phenotypic variation and increases tumor heterogeneity, thus increasing the probability of progress, cancer therapeutic resistance and neoplasm recurrence. Without centrosomes clustering, the tumor cells will die by mitotic catastrophe. Therefore, inhibition of centrosome clustering has become the dawn of cancer therapy, but the mechanism remains little known. We found that radiotherapy and chemotherapy which triggered DNA damage can promote centrosome clustering and cell survival in 5 types of tumors and two cell culture models for study centrosome clustering (TETON-PLK4 stable cells and HU-inducing S-arrest cells with centrosome amplification). DNA damage would trigger KIFC1 through stabling KIFC1 protein levels. Using mass spectrum identification, inhibitors of DNA damage signaling pathway and co-immunoprecipitation, we found that ATM and ATR bind and phosphorylated KIFC1 at Ser26. The phosphorylation of KIFC1-Ser26 promotes centrosome clustering, chromosomal instability (CIN) and chemotherapy drugs-resistance in tumors with centrosome amplification. Thus, the inhibition of KIFC1 Ser26 phosphorylation is necessary for radiotherapy and chemotherapy. In our study, we provide sufficient evidence to show that caffeine and ATM/ATR other inhibitors can promote centrosome de-clustering, multipolar mitosis formation, and mitotic catastrophe. Clinically, KIFC1 has been preliminarily confirmed to associate with malignant transformation and neoplasm recurrence. In summary, we intend to study the crucial role of KIFC1-S26 phosphorylation in drug-resistance and neoplasm recurrence, to provide new targets for the detection of multiple tumors and formulate new intervention strategies.
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The ATM and ATR kinases regulate centrosome clustering and tumor recurrence by targeting KIFC1 phosphorylation.
ATM 和 ATR 激酶通过靶向 KIFC1 磷酸化来调节中心体聚类和肿瘤复发。
DOI:10.1038/s41467-020-20208-x
发表时间:2021-01-04
期刊:Nature communications
影响因子:16.6
作者:Fan G;Sun L;Meng L;Hu C;Wang X;Shi Z;Hu C;Han Y;Yang Q;Cao L;Zhang X;Zhang Y;Song X;Xia S;He B;Zhang S;Wang C
通讯作者:Wang C
DOI:10.1038/s41467-023-42025-8
发表时间:2023-10-20
期刊:NATURE COMMUNICATIONS
影响因子:16.6
作者:Sun, Lianhui;Zhang, Yuan;Yang, Boyu;Sun, Sijun;Zhang, Pengshan;Luo, Zai;Feng, Tingting;Cui, Zelin;Zhu, Ting;Li, Yuming;Qiu, Zhengjun;Fan, Guangjian;Huang, Chen
通讯作者:Huang, Chen
载脂蛋白APOC2乳酰化修饰调控及其促进肿瘤转移的机制研究
  • 批准号:
    --
  • 项目类别:
    面上项目
  • 资助金额:
    53万元
  • 批准年份:
    2022
  • 负责人:
    范广建
  • 依托单位:
肿瘤抑制因子KLF14参与细胞有丝分裂灾变促进肿瘤治疗的机制研究
  • 批准号:
    81602616
  • 项目类别:
    青年科学基金项目
  • 资助金额:
    19.0万元
  • 批准年份:
    2016
  • 负责人:
    范广建
  • 依托单位:
国内基金
海外基金