Hsp90 inhibition increases p53 expression and destabilizes MYCN and MYC in neuroblastoma
Hsp90 inhibition increases p53 expression and destabilizes MYCN and MYC in neuroblastoma
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DOI：
10.3892/ijo_00000829
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发表时间：
2011-01-01
影响因子：
5.2
通讯作者：
Tang, Xao X.
中科院分区：
文献类型：
--
作者：
Regan, Paul L.;Jacobs, Joshua;Tang, Xao X.
神经母细胞瘤是一种表现出有利或不利表型的儿童癌症。 MYCN 和 MYC 是癌蛋白，在确定不良神经母细胞瘤的恶性程度方面发挥着至关重要的作用。 Hsp90 超级伴侣复合物有助于多种致癌客户蛋白的折叠和功能。小分子抑制剂对 Hsp90 的抑制会导致这些致癌蛋白不稳定，从而抑制肿瘤恶性肿瘤。尽管如此，关于 Hsp90 抑制对 MYCN 和 MYC 蛋白稳定性的影响知之甚少。在本研究中，我们研究了 Hsp90 抑制对不利神经母细胞瘤细胞表型的影响，包括其对 MYCN 和 MYC 表达的影响。使用两种 MYCN 扩增的神经母细胞瘤细胞系（IMR5 和 CHP134）和两种非 MYCN 扩增的细胞系（SY5Y 和 SKNAS）来研究 Hsp90 抑制对神经母细胞瘤恶性表型的影响。研究发现，神经母细胞瘤细胞系中的 Hsp90 抑制导致显着的生长抑制、MYCN 和 MYC 表达减少以及 p53 表达增加。在 TP53 突变的 SKNAS 细胞系中，Hsp90 抑制增强了有利的神经母细胞瘤基因 EFNB2、MIZ-1 和 NTRK1 (TrkA) 的表达。此外，Hsp90 抑制降低了 HDAC6 表达并增强了微管蛋白乙酰化。我们的数据共同表明，Hsp90 抑制通过多种细胞途径抑制神经母细胞瘤的生长，并且 MYC/MYCN 不稳定是 Hsp90 抑制的重要后果之一。
Neuroblastoma is a childhood cancer that exhibits either a favorable or an unfavorable phenotype. MYCN and MYC are oncoproteins that play crucial roles in determining the malignancy of unfavorable neuroblastoma. The Hsp90 superchaperone complex assists in the folding and function of a variety of oncogenic client proteins. Inhibition of Hsp90 by small molecule inhibitors leads to the destabilization of these oncogenic proteins and consequently suppresses tumor malignancy. Nonetheless, little is known about the effect of Hsp90 inhibition on the stability of MYCN and MYC proteins. In this study, we investigated the effect of Hsp90 inhibition on the phenotype of unfavorable neuroblastoma cells including its effect on MYCN and MYC expression. Two MYCN-amplified neuroblastoma cell lines (IMR5 and CHP134) and two non-MYCN-amplified cell lines (SY5Y and SKNAS) were used to address the effect of Hsp90 inhibition on the malignant phenotype of neuroblastoma. It was found that Hsp90 inhibition in neuroblastoma cell lines resulted in significant growth suppression, a decrease in MYCN and MYC expression, and an increase in the expression of p53. In the TP53-mutated SKNAS cell line, Hsp90 inhibition enhanced the expression of the favorable neuroblastoma genes EFNB2, MIZ-1 and NTRK1 (TrkA). In addition, Hsp90 inhibition reduced HDAC6 expression and enhanced tubulin acetylation. Together our data suggest that Hsp90 inhibition suppresses the growth of neuroblastoma through multiple cellular pathways and that MYC/MYCN destabilization is among the important consequences of Hsp90 inhibition.