IRE1α-XBP1 inhibitors exerted anti-tumor activities in Ewing's sarcoma.
IRE1α-XBP1 inhibitors exerted anti-tumor activities in Ewing's sarcoma.
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DOI：
10.18632/oncotarget.24467
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发表时间：
2018-03-06
期刊：
影响因子：
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通讯作者：
Saito T
中科院分区：
文献类型：
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作者：
Tanabe Y;Suehara Y;Kohsaka S;Hayashi T;Akaike K;Mukaihara K;Kurihara T;Kim Y;Okubo T;Ishii M;Kazuno S;Kaneko K;Saito T
尤文氏肉瘤 (ES) 是第二常见的儿童骨肿瘤。染色体易位 t(11;22)(q24:q12) 导致 EWS/FLI1 基因融合的形成，这种融合在约 90% 的尤文家族肿瘤中都能检测到。一些转录组研究提供了与 EWS/FLI1 表达相关的基因列表。然而，与 EWS/FLI1 相关的蛋白质表达谱尚未阐明。在这项研究中，为了鉴定与 EWS/FLI1 相关的调节蛋白和 ES 中的治疗靶点，我们在表达 EWS/FLI1 的四种尤文肉瘤细胞系和人间充质干细胞 (hMSC) 中使用 EWS/FLI1 敲低进行了蛋白质组学研究。用于相对和绝对定量 (i-TRAQ) 分析的同量异位标签鉴定出 2,000 多种受 EWS/FLI1 融合蛋白调节的蛋白质。此外，网络分析还确定了几个关键途径，包括排名最高的 XBP1。 XBP1 是一种众所周知的蛋白质，通过 IRE1α-XBP1 途径在未折叠蛋白对内质网 (ER) 应激的反应 (UPR) 中发挥重要作用。我们证实了XBP1（剪接的XBP1和未剪接的XBP1）在手术样本和ES细胞系中的高mRNA表达。 XBP1 的沉默显着抑制了 ES 细胞系中的细胞活力。在使用 IRE1α-XBP1 抑制剂（包括丰加霉素）的抑制剂测定中，我们证实这些药物显着抑制细胞活力，导致体外和体内 ES 细胞凋亡。我们的研究结果表明 IRE1α-XBP1 抑制剂可能有助于开发 ES 的新治疗策略。
Ewing's sarcoma (ES) is the second-most frequent pediatric bone tumor. Chromosomal translocation t(11;22)(q24:q12) results in the formation of EWS/FLI1 gene fusion, which is detected in approximately 90% of tumors of the Ewing family. Several transcriptome studies have provided lists of genes associated with EWS/FLI1 expression. However, the protein expression profiles associated with EWS/FLI1 have yet to be elucidated. In this study, to identify the regulated proteins associated with EWS/FLI1 and therapeutic targets in ES, we conducted proteomic studies using EWS/FLI1 knockdown in four Ewing's sarcoma cell lines and human mesenchymal stem cells (hMSCs) expressing EWS/FLI1. Isobaric tags for relative and absolute quantitation (i-TRAQ) analyses identified more than 2,000 proteins regulated by the EWS/FLI1 fusion. In addition, the network analyses identified several critical pathways, including XBP1, which was ranked the highest. XBP1 is a protein well known to play an important role in the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress through the IRE1α-XBP1 pathway. We confirmed the high mRNA expression of XBP1 (spliced XBP1 and unspliced XBPl) in surgical samples and cell lines in ES. The silencing of XBP1 significantly suppressed the cell viabilities in ES cell lines. In the inhibitor assays using IRE1α-XBP1 inhibitors, including toyocamycin, we confirmed that these agents significantly suppressed the cell viabilities, leading to apoptosis in ES cells both in vitro and in vivo. Our findings suggested that IRE1α-XBP1 inhibitors might be useful for developing novel therapeutic strategies in ES.