Small interfering RNA-Induced CHFR silencing sensitizes oral squamous cell cancer cells to microtubule inhibitors
Small interfering RNA-Induced CHFR silencing sensitizes oral squamous cell cancer cells to microtubule inhibitors
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DOI：
10.4161/cbt.4.7.1896
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发表时间：
2005-07-01
影响因子：
3.6
通讯作者：
Tokino, T
中科院分区：
文献类型：
--
作者：
Ogi, K;Toyota, M;Tokino, T
在口腔鳞状细胞癌（OSCC）中经常检测到细胞周期检查点功能的改变，并且通常与癌细胞对化疗药物的敏感性有关。最近，有丝分裂检查点基因 Chfr 在多种人类肿瘤中被证明因启动子甲基化和点突变而失活。在这里，我们证明其产物 CHFR 的缺失与有丝分裂检查点功能障碍有关，并且缺乏 CHFR 的癌细胞对微管抑制剂敏感。在这种情况下，检查点损伤似乎是由前期缺陷引起的，因为缺乏 CHFR 的 OSCC 细胞显示 Ser10 上的组蛋白 H3 磷酸化以及细胞周期蛋白 B1 易位至细胞核。当用微管抑制剂（多西紫杉醇或紫杉醇）处理 CHFR 缺陷的 OSCC 细胞时，观察到大量凋亡细胞。此外，使用小干扰RNA（siRNA）破坏CHFR会损害有丝分裂检查点，从而降低OSCC细胞停滞在G（2）/M期的能力，并使它们对微管抑制剂更加敏感。我们的结果表明 CHFR 可能是化疗的有用分子靶点。
Alterations in the function of cell cycle checkpoints are frequently detected in oral squamous cell carcinomas (OSCCs), and are often associated with the sensitivity of the cancer cells to chemotherapeutic drugs. Recently, a mitotic checkpoint gene, Chfr, was shown to be inactivated by promoter methylation and point mutations in various human tumors. Here we show that the absence of its product, CHFR, is associated with mitotic checkpoint dysfunction, and that cancer cells lacking CHFR are sensitive to microtubule inhibitors. Checkpoint impairment appears to be caused by a prophase defect in this case, as OSCC cells lacking CHFR showed phosphorylation of histone H3 on Ser10 and translocation of cyclin B1 to the nucleus. When CHFR-deficient OSCC cells were treated with a microtubule inhibitor (docetaxel or paclitaxel), significant numbers of apoptotic cells were observed. Moreover, disruption of CHFR using small interfering RNA (siRNA) impaired the mitotic checkpoint, thereby reducing the ability of OSCC cells to arrest at G(2)/M phase and making them more sensitive to microtubule inhibitors. Our results suggest that CHFR could be a useful molecular target for chemotherapy.