Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells
Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells
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DOI：
10.1073/pnas.1031523100
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发表时间：
2003-05-13
影响因子：
11.1
通讯作者：
Erikson, RL
中科院分区：
文献类型：
--
作者：
Liu, XQ;Erikson, RL
哺乳动物polo样激酶（PIk）1的表达升高发生在许多不同类型的癌症中，并且PIk1已被提出作为几种肿瘤的新诊断标志物。我们使用最近开发的基于载体的小干扰RNA技术特异性地消耗癌细胞中的PIk1。我们发现，PIk1缺失显著抑制细胞增殖，降低活力，并导致细胞周期停滞与4n DNA含量。哑铃状染色质结构的形成表明这些细胞在后期开始时无法完全分离姐妹染色单体。荧光激活细胞分选仪（FACS）中亚基因组DNA的出现、caspase 3的激活和碎片化细胞核的形成表明，PIk1缺失诱导细胞凋亡。通过共转染不可降解的小鼠PIk1构建物，部分逆转了PIk1耗竭诱导的细胞凋亡。此外，p53通路被证明参与了pik1耗竭诱导的细胞凋亡。DNA损伤发生在PIk1缺失的细胞中，抑制ATM强烈增强了PIk1缺失的致命性。尽管p53在pik1缺失的细胞中是稳定的，但DNA损伤也发生在p53（-/-）细胞中。这些数据支持这样一种观点，即破坏PIk1功能可能是癌症治疗中的一个重要应用。
Elevated expression of mammalian polo-like kinase (PIk)1 occurs in many different types of cancers, and PIk1 has been proposed as a novel diagnostic marker for several tumors. We used the recently developed vector-based small interfering RNA technique to specifically deplete PIk1 in cancer cells. We found that PIk1 depletion dramatically inhibited cell proliferation, decreased viability, and resulted in cell-cycle arrest with 4 N DNA content. The formation of dumbbell-like chromatin structure suggests the inability of these cells to completely separate the sister chromatids at the onset of anaphase. PIk1 depletion induced apoptosis, as indicated by the appearance of subgenomic DNA in fluorescence-activated cell-sorter (FACS) profiles, the activation of caspase 3, and the formation of fragmented nuclei. PIk1-depletion-induced apoptosis was partially reversed by cotransfection of nondegradable mouse PIk1 constructs. In addition, the p53 pathway was shown to be involved in PIk1-depletion-induced apoptosis. DNA damage occurred in PIk1-depleted cells and inhibition of ATM strongly potentiated the lethality of PIk1 depletion. Although p53 is stabilized in PIk1-depleted cells, DNA damage also occurs in p53(-/-) cells. These data support the notion that disruption of PIk1 function could be an important application in cancer therapy.