Nek4 status differentially alters sensitivity to distinct microtubule poisons.
Nek4 status differentially alters sensitivity to distinct microtubule poisons.
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DOI：
10.1158/0008-5472.can-09-2113
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发表时间：
2010-02-01
期刊：
影响因子：
11.2
通讯作者：
Hemann MT
中科院分区：
文献类型：
--
作者：
Doles J;Hemann MT
虽然微管毒物通常用于治疗各种恶性肿瘤，但对决定这些药物相对疗效的细胞因子知之甚少。在这里，我们确定了NIMA激酶，Nek 4，在遗传筛选介质的响应前线化疗紫杉醇。为了确定Nek 4缺陷细胞中紫杉醇抗性的潜在机制，我们检测了Nek 4在有丝分裂和微管稳态中的功能。值得注意的是，我们发现Nek 4促进瞬时解聚后的微管生长。此外，缺乏Nek 4的细胞在紫杉醇处理后表现出受损的G2/M期阻滞，以及有丝分裂样星形细胞减少，进一步表明Nek 4在微管组装调节中的作用。有趣的是，Nek 4抑制也使癌细胞对长春新碱敏感，长春新碱是另一种具有独特作用机制的微管毒物。因此，Nek 4缺乏可能拮抗或促进微管毒物的作用，这取决于单个药物是否使微管聚合物超稳定或低稳定。虽然这种现象以前已经记录了携带特定微管蛋白突变的细胞，但这些数据提供了另一个例子，说明在特定肿瘤中促进耐药性的改变如何同时增强另一种类似的常规化疗剂的疗效。值得注意的是，Nek 4位于非小细胞肺癌中通常缺失的基因组位点。因此，这些数据也表明了在特定肺癌患者中选择性使用特定微管毒物的基本原理。
While microtubule poisons are commonly used for the treatment of diverse malignancies, relatively little is known about cellular factors that determine the relative efficacy of these drugs. Here, we identified the NIMA kinase, Nek4, in a genetic screen for mediators of the response to the front-line chemotherapeutic taxol. To identify the mechanism underlying taxol resistance in Nek4-deficient cells, we examined Nek4 function in mitosis and microtubule homeostasis. Notably, we found that Nek4 promotes microtubule outgrowth following transient depolymerization. Additionally, cells lacking Nek4 showed an impaired G2/M arrest following taxol treatment, as well as a decrease in mitotic-like asters, further suggesting a role for Nek4 in the regulation of microtubule assembly. Interestingly, Nek4 suppression also sensitized cancer cells to vincristine, another microtubule poison with a distinct mechanism of action. Therefore, Nek4 deficiency may either antagonize or promote the effects of microtubule poisons, depending on whether an individual drug hyper- or hypo-stabilizes microtubule polymers. While this phenomenon has previously been documented for cells bearing specific tubulin mutations, these data provide yet another example of how an alteration promoting drug resistance in a particular tumor can simultaneously enhance the efficacy of another, similar conventional chemotherapeutic. Of note, Nek4 is located in a commonly deleted genomic locus in non-small cell lung cancer. Consequently, these data also suggest a rationale for the selective use of particular microtubule poisons in specific lung cancer patients.