Phosphorylation and activation of cell division cycle associated 8 by aurora kinase B plays a significant role in human lung carcinogenesis
Phosphorylation and activation of cell division cycle associated 8 by aurora kinase B plays a significant role in human lung carcinogenesis
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DOI：
10.1158/0008-5472.can-06-4705
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发表时间：
2007-05-01
期刊：
影响因子：
11.2
通讯作者：
Nakamura, Yusuke
中科院分区：
文献类型：
--
作者：
Hayama, Satoshi;Daigo, Yataro;Nakamura, Yusuke
通过肺癌全基因组基因表达分析，我们在绝大多数肺癌样本中检测到细胞分裂周期相关8（CDCA8）和极光激酶B（AURKB）的共反式激活，它们被认为是脊椎动物染色体过客复合物的组成部分。肺癌组织芯片的免疫组织化学分析表明CDCA8和AURKB的过表达与肺癌患者的不良预后显着相关。 AURKB 直接磷酸化 CDCA8 Ser(154)、Ser(219)、Ser(275) 和 Thr(278)，并且似乎可以稳定癌细胞中的 CDCA8 蛋白。用针对CDCA8的小干扰RNA抑制CDCA8表达显着抑制了肺癌细胞的生长。此外，通过与CDCA8部分的20个氨基酸序列相对应的细胞渗透肽(11R-CDCA8(261-280))对CDCA8和AURKB之间的相互作用进行功能性抑制，其中包括AURKB的两个磷酸化位点，显着降低CDCA8的磷酸化并导致肺癌细胞的生长抑制。我们的数据表明，选择性抑制 CDCA8-AURKB 通路可能是治疗肺癌患者的一种有前途的治疗策略。
Through genome-wide gene expression analysis of lung carcinomas, we detected in the great majority of lung cancer samples cotransactivation of cell division cycle associated 8 (CDCA8) and aurora kinase B (AURKB), which were considered to be components of the vertebrate chromosomal passenger complex. Immunohistochemical analysis of lung cancer tissue microarrays showed that overexpression of CDCA8 and AURKB was significantly associated with poor prognosis of lung cancer patients. AURKB directly phosphorylated CDCA8 at Ser(154), Ser(219), Ser(275), and Thr(278) and seemed to stabilize CDCA8 protein in cancer cells. Suppression of CDCA8 expression with small interfering RNA against CDCA8 significantly suppressed the growth of lung cancer cells. In addition, functional inhibition of interaction between CDCA8 and AURKB by a cell-permeable peptide corresponding to 20amino acid sequence of a part of CDCA8 (11R-CDCA8(261-280)), which included two phosphorylation sites by AURKB, significantly reduced phosphorylation of CDCA8 and resulted in growth suppression of lung cancer cells. Our data imply that selective suppression of the CDCA8-AURKB pathway could be a promising therapeutic strategy for treatment of lung cancer patients.