Therapeutic potential of targeting IRES-dependent c-myc translation in multiple myeloma cells during ER stress.
Therapeutic potential of targeting IRES-dependent c-myc translation in multiple myeloma cells during ER stress.
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在ER应激期间，在多个骨髓瘤细胞中靶向IRES依赖性C-MYC翻译的治疗潜力。
DOI：
10.1038/onc.2015.156
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发表时间：
2016-02-25
期刊：
影响因子：
8
通讯作者：
Lichtenstein A
中科院分区：
文献类型：
--
作者：
Shi Y;Yang Y;Hoang B;Bardeleben C;Holmes B;Gera J;Lichtenstein A
未折叠蛋白反应(UPR)诱导的eIF-2α磷酸化抑制了蛋白质翻译，以保护其免受内质网(ER)应激。此外，我们还发现，由于内质网应激多发性骨髓瘤(MM)细胞中mTORC1活性降低，蛋白质翻译受到额外的抑制。然而，c-myc蛋白水平和myc翻译保持不变。为了确定c-myc是如何维持的，我们研究了不需要mTORC1活性的myc IRES功能。在thapsigargin、衣霉素或骨髓瘤治疗药物bortezomib诱导的内质网应激过程中，MM细胞MYC IRES活性上调。IRES活性依赖于上游MAPK和MNK1信号。筛选发现hnRNP A1(A1)和RPS 25是ER应激激活活动所需的IRES结合反式因子。在内质网应激过程中，A1与RPS25相关，这可被MNK抑制剂阻止。在一个原理的证明中，我们确定了一种化合物，它阻止A1与myc IRES的结合，并特异性地抑制MM细胞中的myc IRES活性。这种化合物单独使用时，不具有细胞毒性，也不抑制myc翻译或蛋白表达。然而，当与内质网应激诱导剂，特别是Bortezomib联合使用时，显著的协同细胞毒作用伴随着对myc翻译和表达的抑制。这些结果强调了在内质网应激期间靶向A1介导的MM细胞myc IRES活性的可能性。
Protein translation is inhibited by the unfolded protein response (UPR)-induced eIF-2α phosphorylation to protect against endoplasmic reticulum (ER) stress. In addition, we found additional inhibition of protein translation due to diminished mTORC1 activity in ER-stressed multiple myeloma (MM) cells. However, c-myc protein levels and myc translation was maintained. To ascertain how c-myc was maintained, we studied myc IRES function which does not require mTORC1 activity. Myc IRES activity was upregulated in MM cells during ER stress induced by thapsigargin, tunicamycin or the myeloma therapeutic bortezomib. IRES activity was dependent upon upstream MAPK and MNK1 signaling. A screen identified hnRNP A1 (A1) and RPS 25 as IRES-binding trans factors required for ER stress-activated activity. A1 associated with RPS25 during ER stress and this was prevented by a MNK inhibitor. In a proof of principle, we identified a compound that prevented binding of A1 to the myc IRES and specifically inhibited myc IRES activity in MM cells. This compound, when used alone, was not cytotoxic nor did it inhibit myc translation or protein expression. However, when combined with ER stress inducers, especially bortezomib, a remarkable synergistic cytotoxicity ensued with associated inhibition of myc translation and expression. These results underscore the potential for targeting A1-mediated myc IRES activity in MM cells during ER stress.