Akt-dependent nuclear localization of Y-box-binding protein 1 in acquisition of malignant characteristics by human ovarian cancer cells
Akt-dependent nuclear localization of Y-box-binding protein 1 in acquisition of malignant characteristics by human ovarian cancer cells
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DOI：
10.1038/sj.onc.1210084
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发表时间：
2007-04-26
期刊：
影响因子：
8
通讯作者：
Kuwano, M.
中科院分区：
文献类型：
--
作者：
Basaki, Y.;Hosoi, F.;Kuwano, M.
Y 盒结合蛋白 1 (YB-1) 是含有冷休克结构域的 DNA 结合蛋白家族的成员，具有响应各种环境刺激的多效性功能。正如我们之前所表明的，YB-1 是卵巢癌和其他肿瘤类型的多药耐药性的全球标志物。为了鉴定卵巢癌中 YB-1 调节的基因，我们使用高密度寡核苷酸阵列研究了 YB-1 小干扰 RNA (siRNA) 转染的卵巢癌细胞的表达谱。 siRNA敲低YB-1上调344个基因，包括MDR1、胸苷酸合成酶、S100钙结合蛋白和细胞周期蛋白B，下调534个基因，包括CXCR4、N-myc下游调节基因1、E-钙粘蛋白和磷脂酶C。外源血清添加刺激YB-1从细胞质易位到细胞核，以及用Akt抑制剂和Akt治疗siRNA 和整合素连接激酶 (ILK) siRNA 特异性阻断 YB-1 核定位。抑制 Akt 激活可下调 CXCR4 并上调 MDR1 (ABCB1) 基因表达。在异种移植动物模型中，使用 Akt 抑制剂可导致核 YB-1 阳性癌细胞减少。 Akt 激活从而调节 YB-1 的核转位，影响耐药基因和其他与卵巢癌细胞恶性特征相关的基因的表达。因此，Akt 通路可能成为破坏 YB-1 核转位的新靶点，这对于进一步开发卵巢癌治疗策略具有重要意义。
Y-box-binding protein 1 (YB-1), which is a member of the DNA-binding protein family containing a cold-shock domain, has pleiotropic functions in response to various environmental stimuli. As we previously showed that YB-1 is a global marker of multidrug resistance in ovarian cancer and other tumor types. To identify YB-1-regulated genes in ovarian cancers, we investigated the expression profile of YB-1 small-interfering RNA (siRNA)-transfected ovarian cancer cells using a high-density oligonucleotide array. YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. Exogenous serum addition stimulated YB-1 translocation from the cytoplasm to the nucleus, and treatment with Akt inhibitors as well as Akt siRNA and integrin-linked kinase (ILK) siRNA specifically blocked YB-1 nuclear localization. Inhibition of Akt activation downregulated CXCR4 and upregulated MDR1 (ABCB1) gene expression. Administration of Akt inhibitor resulted in decrease in nuclear YB-1-positive cancer cells in a xenograft animal model. Akt activation thus regulates the nuclear translocation of YB-1, affecting the expression of drug-resistance genes and other genes associated with the malignant characteristics in ovarian cancer cells. Therefore, the Akt pathway could be a novel target of disrupting the nuclear translocation of YB-1 that has important implications for further development of therapeutic strategy against ovarian cancers.