Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Xue Yuan Road 38, Beijing 100191, PR China.
Biochem Biophys Res Commun. 2012 Apr 27;421(1):44-50. doi: 10.1016/j.bbrc.2012.03.105. Epub 2012 Mar 27.
Lidamycin is a potential anti-cancer drug, which is widely used in a variety of human cancer types. It has been reported that lidamycin inhibited mouse embryonic carcinoma (EC) cells growth through down-regulation of embryonic stem (ES) cell-like genes. In this study, whether 0.01 nM lidamycin induces neuronal differentiation of mouse EC cells was investigated. It was observed that lidamycin decreased transcription factor Oct4, and increased both p21 mRNA and protein expression in P19 EC cells. Furthermore, luciferase assay showed that lidamycin activated p21 promoter activity through suppression of Oct4, and Chromatin immunoprecipitation (ChIP) assay confirmed that binding of transcription factor Oct4 to the p21 promoter decreased in lidamycin-exposed cells. Knockdown of Oct4 resulted in neuron-like differentiation and up-regulation of p21 expression. In accordance, overexpression of Oct4 blocked neural differentiation and down-regulated p21 in lidamycin-treated P19 cells. Taken together, these results suggested that neuronal differentiation of EC cells induced by lidamycin was associated with the inhibition of Oct4 expression and the activation of p21 transcription. Our results have provided a novel mechanism, in which lidamycin led to cancer cell differentiation.
力达霉素是一种潜在的抗癌药物，广泛用于多种人类癌症类型。据报道，力达霉素通过下调胚胎干细胞（ES）样基因抑制小鼠胚胎癌细胞（EC）的生长。在本研究中，研究了 0.01 nM 力达霉素是否诱导小鼠 EC 细胞的神经元分化。结果观察到力达霉素降低转录因子 Oct4 的表达，并增加 P19 EC 细胞中 p21 mRNA 和蛋白的表达。此外，荧光素酶报告基因检测显示，力达霉素通过抑制 Oct4 激活 p21 启动子活性，染色质免疫沉淀（ChIP）实验证实力达霉素处理的细胞中转录因子 Oct4 与 p21 启动子的结合减少。Oct4 的敲低导致神经元样分化和 p21 的上调。相应地，Oct4 的过表达阻断了 lidamycin 处理的 P19 细胞中的神经分化并下调了 p21。总之，这些结果表明，力达霉素诱导的 EC 细胞神经元分化与 Oct4 表达的抑制和 p21 转录的激活有关。我们的研究结果提供了一种新的机制，即力达霉素导致癌细胞分化。
