Small molecule targeting the Hec1/Nek2 mitotic pathway suppresses tumor cell growth in culture and in animal.
Small molecule targeting the Hec1/Nek2 mitotic pathway suppresses tumor cell growth in culture and in animal.
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DOI：
10.1158/0008-5472.can-08-1915
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发表时间：
2008-10-15
期刊：
影响因子：
11.2
通讯作者：
Lee WH
中科院分区：
文献类型：
--
作者：
Wu G;Qiu XL;Zhou L;Zhu J;Chamberlin R;Lau J;Chen PL;Lee WH
Hec 1是一种保守的有丝分裂调节因子，对纺锤体检查点控制、动粒功能和细胞存活至关重要。Hec 1的过表达已在多种人类癌症中检测到，并与原发性乳腺癌的预后不良有关。通过化学遗传学筛选，我们已经确定了一个小分子，INH 1，它通过直接Hec 1结合特异性破坏Hec 1/Nek 2相互作用。用INH 1处理细胞引发了激动素结合的Hec 1以及整体Nek 2蛋白水平的降低，从而导致中期染色体错位、纺锤体异常和最终的细胞死亡。INH 1能有效抑制多种人乳腺癌细胞株的增殖（GI 50 10~21 μM）。此外，INH 1治疗延缓了荷人乳腺癌细胞系MDA-MB-468异种移植物的裸鼠模型中的肿瘤生长，没有明显的副作用。这项研究表明，Hec 1/Nek 2通路可能作为一个新的有丝分裂靶点，用于小分子化合物的癌症干预。
Hec1 is a conserved mitotic regulator critical for spindle checkpoint control, kinetochore functionality and cell survival. Overexpression of Hec1 has been detected in a variety of human cancers and is linked to poor prognosis of primary breast cancers. Through a chemical genetic screening, we have identified a small molecule, INH1, which specifically disrupts the Hec1/Nek2 interaction via direct Hec1 binding. Treating cells with INH1 triggered reduction of kinetochore-bound Hec1 as well as global Nek2 protein level, consequently leading to metaphase chromosome misalignment, spindle aberrancy and eventual cell death. INH1 effectively inhibited the proliferation of multiple human breast cancer cell lines in culture (GI50 10~21 μM). Furthermore, treatment with INH1 retarded tumor growth in a nude mouse model bearing xenografts derived from the human breast cancer line MDA-MB-468, with no apparent side effects. This study suggests that the Hec1/Nek2 pathway may serve as a novel mitotic target for cancer intervention by small compounds.