Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
Int J Oncol. 2010 Oct;37(4):983-91. doi: 10.3892/ijo_00000749.
Neuroblastoma is a childhood malignancy of the sympathetic nervous system. The tumor exhibits two different phenotypes: favorable and unfavorable. MYCN amplification is associated with rapid tumor progression and the worst neuroblastoma disease outcome. We have previously reported that inhibitors of histone deacetylase (HDAC) and proteasome enhance favorable neuroblastoma gene expression in neuroblastoma cell lines and inhibit growth of these cells. In this study, we investigated the effect of trichostatin A or TSA (an HDAC inhibitor), and epoxomycin (a proteasome inhibitor) on MYCN and p53 expression in MYCN-amplified neuroblastoma cells. It was found that TSA down-regulated MYCN expression, but Epoxomycin and the TSA/Epoxomycin combination led to MYCN hyper-expression in MYCN-amplified neuroblastoma cell lines. Despite their contrasting effects on MYCN expression, TSA and Epoxomycin caused growth suppression and cell death of the MYCN-amplified cell lines examined. Consistent with these data, forced hyper-expression of MYCN in MYCN-amplified IMR5 cells via transfection resulted in growth suppression and the increased expression of several genes known to suppress growth or induce cell death. Furthermore, Epoxomycin as a single agent and its combination with TSA enhance p53 expression in the MYCN-amplified neuroblastoma cell lines. Unexpectedly, co-transfection of TP53 and MYCN in IMR5 cells resulted in high p53 expression but a reduction of MYCN expression. Together our data suggest that either down regulation or hyper-expression of MYCN results in growth inhibition and/or apoptosis of MYCN-amplified neuroblastoma cells. In addition, elevated p53 expression has a suppressive effect on MYCN expression in these cells.
神经母细胞瘤是一种起源于交感神经系统的儿童期恶性肿瘤。该肿瘤表现出两种不同的表型：有利型和不利型。MYCN 扩增与肿瘤的快速进展和最严重的神经母细胞瘤疾病结局相关。我们之前的研究表明，组蛋白去乙酰化酶（HDAC）抑制剂和蛋白酶体抑制剂可增强神经母细胞瘤细胞系中有利型神经母细胞瘤基因的表达，并抑制这些细胞的生长。在这项研究中，我们研究了 Trichostatin A 或 TSA（一种 HDAC 抑制剂）和 Epoxomycin（一种蛋白酶体抑制剂）对 MYCN 扩增型神经母细胞瘤细胞中 MYCN 和 p53 表达的影响。结果发现，TSA 下调了 MYCN 的表达，但 Epoxomycin 和 TSA/Epoxomycin 联合作用导致 MYCN 扩增型神经母细胞瘤细胞系中 MYCN 的过度表达。尽管 TSA 和 Epoxomycin 对 MYCN 表达有相反的影响，但它们都导致了所检测的 MYCN 扩增型细胞系的生长抑制和细胞死亡。与这些数据一致的是，通过转染迫使 MYCN 扩增型 IMR5 细胞中 MYCN 的过度表达导致了生长抑制和几个已知抑制生长或诱导细胞死亡的基因的表达增加。此外，Epoxomycin 作为单一药物及其与 TSA 的联合应用可增强 MYCN 扩增型神经母细胞瘤细胞系中 p53 的表达。出乎意料的是，TP53 和 MYCN 在 IMR5 细胞中的共转染导致高 p53 表达和 MYCN 表达的减少。总之，我们的数据表明，MYCN 的下调或过表达导致 MYCN 扩增型神经母细胞瘤细胞的生长抑制和/或凋亡。此外，这些细胞中 p53 表达的升高对 MYCN 表达具有抑制作用。
