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首页> 外文期刊>Radiotherapy and oncology: Journal of the European Society for Therapeutic Radiology and Oncology >Double targeting of Survivin and XIAP radiosensitizes 3D grown human colorectal tumor cells and decreases migration
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Double targeting of Survivin and XIAP radiosensitizes 3D grown human colorectal tumor cells and decreases migration

机译：Survivin和XIAP的双重靶向使3D生长的人类结直肠肿瘤细胞放射增敏并减少迁移

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Background and purpose In the present study, we aimed to investigate the effect of single and double knockdown of the inhibitor of apoptosis proteins (IAP) Survivin and X-linked IAP (XIAP) on three-dimensional (3D) clonogenic survival, migration capacity and underlying signaling pathways. Materials and methods Colorectal cancer cell lines (HCT-15, SW48, SW480, SW620) were subjected to siRNA-mediated single or Survivin/XIAP double knockdown followed by 3D colony forming assays, cell cycle analysis, Caspase activity assays, migration assays, matrigel transmigration assays and Western blotting (Survivin, XIAP, Focal adhesion kinase (FAK), p-FAK Y397, Akt1, p-Akt1 S473, Extracellular signal-regulated kinase (ERK1/2), p-ERK1/2 T202/Y204, Glycogen synthase kinase (GSK)3β, p-GSK3β S9, nuclear factor (NF)-κB p65). Results While basal cell survival was altered cell line-dependently, Survivin or XIAP single and Survivin/XIAP double knockdown enhanced cellular radiosensitivity of all tested cancer cell lines grown in 3D. Particularly double knockdown conditions revealed accumulation of cells in G2/M, increased subG1 fraction, elevated Caspase 3/7 activity, and reduced migration. Intracellular signaling showed dephosphorylation of FAK and Akt1 upon Survivin and/or Survivin/XIAP silencing. Conclusions Our results strengthen the notion of Survivin and XIAP to act as radiation resistance factors and further indicate that these apoptosis-regulating proteins are also functioning in cell cycling and cell migration.
机译：背景与目的在本研究中，我们旨在研究凋亡蛋白抑制剂（IAP）Survivin和X连锁IAP（XIAP）的单双击对三维（3D）克隆形成存活，迁移能力和潜在的信号通路。材料和方法对结直肠癌细胞系（HCT-15，SW48，SW480，SW620）进行siRNA介导的单或Survivin / XIAP双重敲除，然后进行3D集落形成测定，细胞周期分析，Caspase活性测定，迁移测定，基质胶迁移测定和Western印迹（Survivin，XIAP，局灶性粘附激酶（FAK），p-FAK Y397，Akt1，p-Akt1 S473，细胞外信号调节激酶（ERK1 / 2），p-ERK1 / 2 T202 / Y204，糖原合酶激酶（GSK）3β，p-GSK3βS9，核因子（NF）-κBp65）。结果虽然基础细胞存活率依赖于细胞系而改变，但Survivin或XIAP单和Survivin / XIAP双重敲低可增强所有3D生长的受测试癌细胞系的细胞放射敏感性。特别是双重击倒条件显示细胞在G2 / M中积累，subG1分数增加，Caspase 3/7活性升高和迁移减少。细胞内信号转导显示Survivin和/或Survivin / XIAP沉默后FAK和Akt1的去磷酸化。结论我们的结果加强了Survivin和XIAP作为辐射抗性因子的观念，并进一步表明这些凋亡调节蛋白在细胞周期和细胞迁移中也起作用。

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