Impact of XIAP protein levels on the survival of myeloma cells
Impact of XIAP protein levels on the survival of myeloma cells
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DOI：
10.3324/haematol.13483
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发表时间：
2009-01-01
期刊：
影响因子：
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通讯作者：
Barille-Nion, Sophie
中科院分区：
文献类型：
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作者：
Desplanques, Gregoire;Giuliani, Nicola;Barille-Nion, Sophie
背景XIAP是最具特征和最有效的直接内源性caspase抑制剂，被认为是控制癌细胞凋亡阈值的关键因素。在这份报告中，我们专门讨论XIAP的调节和功能在骨髓瘤cells.Design and MethodsXIAP及其内源性抑制剂XAF-1蛋白水平和它们的调节进行了评估，通过免疫印迹分析在骨髓瘤细胞系或原代骨髓瘤细胞。XIAP敲低RNA干扰被用来评估XIAP在体外，药物敏感性和体内肿瘤growth.ResultsOur结果表明，骨髓瘤细胞表达高水平的XIAP蛋白，在生长因子刺激或应激条件下受到严格调控。值得注意的是，在mTOR抑制剂雷帕霉素阻断典型的帽依赖性翻译期间证明了XIAP水平的增加，支持XIAP mRNA中功能性IRES序列的假设。此外，半胱天冬酶介导的XIAP切割与蛋白酶体抑制剂硼替佐米处理细胞后发生的凋亡过程相关。重要的是，使用RNA干扰敲低XIAP增强了NOD/SCID小鼠的药物敏感性并减少了肿瘤形成。最后，骨髓瘤细胞还表达了XIAP抑制剂XAF-1，与XIAP在可行的myeloma cells.ConclusionsAltogether相互作用，我们的数据主张一个微妙的控制XIAP功能在骨髓瘤细胞和刺激的兴趣，在骨髓瘤治疗中针对XIAP。
BackgroundXIAP is the best characterized and the most potent direct endogenous caspase inhibitor and is considered a key actor in the control of apoptotic threshold in cancer cells. In this report, we specifically addressed XIAP regulation and function in myeloma cells.Design and MethodsXIAP and its endogenous inhibitor XAF-1 protein levels and their regulation were assessed by immunoblot analysis in myeloma cell lines or primary myeloma cells. XIAP knockdown by RNA interference was used to evaluate XIAP impact on in vitro, drug sensitivity and in vivo tumor growth.ResultsOur results indicate that myeloma cells expressed high levels of XIAP protein that were tightly regulated during growth factor stimulation or stress condition. Of note, an increased XIAP level was evidenced during the blockade of the canonical cap-dependent translation by the mTOR inhibitor rapamycin, supporting the hypothesis of a functional IRES sequence in XIAP mRNA. In addition, caspase-mediated XIAP cleavage correlated to an apoptotic process occurring upon cell treatment with the proteasome inhibitor bortezomib. Importantly, XIAP knockdown using RNA interference enhanced drug sensitivity and decreased tumor formation in NOD/SCID mice. Finally, myeloma cells also expressed the XIAP inhibitor XAF-1 that interacted with XIAP in viable myeloma cells.ConclusionsAltogether, our data argue for a delicate control of XIAP function in myeloma cells and stimulate interest in targeting XIAP in myeloma treatment.