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17-AAG对MYCN扩增的神经母细胞瘤细胞中HSP90抑制的治疗效果的新机制

A Novel Mechanism of 17-AAG Therapeutic Efficacy on HSP90 Inhibition in MYCN-Amplified Neuroblastoma Cells.

作者信息

Hanna Reine, Abdallah Jad, Abou-Antoun Tamara

机构信息

Faculty of Sciences, Lebanese University, Fanar, Lebanon.

School of Pharmacy, Lebanese American University, Byblos, Lebanon.

出版信息

Front Oncol. 2021 Jan 25;10:624560. doi: 10.3389/fonc.2020.624560. eCollection 2020.

DOI:10.3389/fonc.2020.624560
PMID:33569349
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7868539/
Abstract

BACKGROUND

Neuroblastoma is the most common pediatric extra-cranial nervous system tumor, originating from neural crest elements and giving rise to tumors in the adrenal medulla and sympathetic chain ganglia. Amplification of MYCN confers increased malignancy and poorer prognosis in high-risk neuroblastoma. Our SILAC proteomics analysis revealed over-expression of HSP90 in MYCN-amplified IMR-32 compared to the non-MYCN amplified SK-N-SH human neuroblastoma cells, rendering them highly resistant to therapeutic intervention.

METHODS

We used cellular bio-functional (proliferation, migration/invasion, apoptosis, viability and stem-cell self-renewal) assays and Western blot analysis to elucidate the therapeutic efficacy of HSP90 inhibition with 17-AAG.

RESULTS

17-AAG treatment significantly inhibited cellular proliferation, viability and migration/invasion and increased apoptosis in both cell lines. Moreover, drug treatment significantly abrogated stem-cell self-renewal potential in the MYCN-amplified IMR-32 cells. Differential tumorigenic protein expression revealed a novel mechanism of therapeutic efficacy after 17-AAG treatment with a significant downregulation of HMGA1, FABP5, Oct4, MYCN, prohibitin and p-L1CAM in SK-N-SH cells. However, we observed a significant up-regulation of p-L1CAM, MYCN and prohibitin, and significant down-regulation of Oct4, FABP5, HMGA1, p-ERK, cleaved/total caspase-3 and PARP1 in IMR-32 cells.

CONCLUSIONS

HSP90 inhibition revealed a novel therapeutic mechanism of antitumor activity in MYCN-amplified neuroblastoma cells that may enhance therapeutic sensitivity.

摘要

背景

神经母细胞瘤是最常见的小儿颅外神经系统肿瘤，起源于神经嵴细胞，可在肾上腺髓质和交感神经链神经节形成肿瘤。MYCN基因扩增会导致高危神经母细胞瘤的恶性程度增加且预后较差。我们的稳定同位素标记氨基酸细胞培养定量蛋白质组学分析显示，与未扩增MYCN的SK-N-SH人神经母细胞瘤细胞相比，在扩增MYCN的IMR-32细胞中HSP90表达上调，这使得它们对治疗干预具有高度抗性。

方法

我们使用细胞生物功能（增殖、迁移/侵袭、凋亡、活力和干细胞自我更新）检测和蛋白质免疫印迹分析来阐明17-AAG抑制HSP90的治疗效果。

结果

17-AAG处理显著抑制了两种细胞系的细胞增殖、活力以及迁移/侵袭，并增加了细胞凋亡。此外，药物处理显著消除了扩增MYCN的IMR-32细胞中的干细胞自我更新潜能。差异致瘤蛋白表达揭示了17-AAG处理后治疗效果的新机制，即SK-N-SH细胞中HMGA1、FABP5、Oct4、MYCN、抑制素和磷酸化L1细胞黏附分子（p-L1CAM）显著下调。然而，我们观察到IMR-32细胞中p-L1CAM、MYCN和抑制素显著上调，而Oct4、FABP5、HMGA1、磷酸化细胞外信号调节激酶（p-ERK）、裂解/总半胱天冬酶-3和聚（ADP-核糖）聚合酶1（PARP1）显著下调。

结论

HSP90抑制揭示了扩增MYCN的神经母细胞瘤细胞中抗肿瘤活性的新治疗机制，这可能会增强治疗敏感性。

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