Arsenic trioxide disturbs the LIS1/NDEL1/dynein microtubule dynamic complex by disrupting the CLIP170 zinc finger in head and neck cancer.
Arsenic trioxide disturbs the LIS1/NDEL1/dynein microtubule dynamic complex by disrupting the CLIP170 zinc finger in head and neck cancer.
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三氧化二砷通过破坏头颈癌中的 CLIP170 锌指来扰乱 LIS1/NDEL1/动力蛋白微管动态复合物
DOI：
10.1016/j.taap.2020.115158
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发表时间：
2020-09-15
影响因子：
3.8
通讯作者：
Liu KJ
中科院分区：
文献类型：
--
作者：
Gao L;Xue B;Xiang B;Liu KJ
癌症死亡主要是由转移引起的，转移需要微管等细胞骨架成分的动态重塑。针对微管提出了一种有前景的抗转移策略，可以防止癌症扩散和复发。众所周知，三氧化二砷（ATO）能够抑制实体恶性肿瘤的迁移和侵袭，但其确切的分子机制尚不清楚。在这里，我们报告了 ATO 在头颈鳞状细胞癌 (HNSCC) 中的新分子靶点和抗转移机制。我们发现与正常对照相比，细胞质连接蛋白 170 (CLIP170) 在 HNSCC 组织和细胞中过度表达。非细胞毒性水平的 ATO (1 μM) 通过取代 CLIP170 锌指基序中的锌来抑制 HNSCC 细胞的迁移和侵袭，CLIP170 是控制微管动力学的关键蛋白。 ATO 的抗转移作用与 siRNA 介导的 CLIP170 敲低的效果相当。此外，ATO 通过 Cal27 细胞中的 CLIP170/LIS1/NDEL1/dynein 信号通路失调微管聚合，这是 CLIP170 锌指破坏的功能结果。补充锌可以部分逆转这种影响。总而言之，这些发现表明 CLIP170 是 ATO 的一个新分子靶点，并证明了 ATO 作为 HNSCC 治疗的潜在抗转移剂的能力和潜在机制。
Cancer mortality is mainly caused by metastasis, which requires dynamic remodeling of cytoskeletal components such as microtubules. Targeting microtubules presents a promising antimetastatic strategy that could prevent cancer spreading and recurrence. It is known that arsenic trioxide (ATO) is able to inhibit the migration and invasion of solid malignant tumors, but its exact molecular mechanism remains unclear. Here, we report a novel molecular target and antimetastatic mechanism of ATO in head and neck squamous cell carcinoma (HNSCC). We found that cytoplasmic linker protein 170 (CLIP170) was overexpressed in HNSCC tissues and cells compared to normal controls. ATO at non-cytotoxic level (1 μM) inhibited the migration and invasion of HNSCC cells by displacing zinc in the zinc finger motif of CLIP170, which is a key protein that controls microtubule dynamics. The antimetastatic effects of ATO were equivalent to those of siRNA-mediated CLIP170 knockdown. Furthermore, ATO dysregulated microtubule polymerization via the CLIP170/LIS1/NDEL1/dynein signaling pathway in Cal27 cells as a functional consequence of CLIP170 zinc finger disruption. The effect was partially reversed by zinc supplementation. Taken together, these findings reveal that CLIP170 is a novel molecular target of ATO and demonstrate the capability and underlying mechanisms of ATO as a potential antimetastatic agent for HNSCC treatment.
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影响因子：
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