Inhibition of All-Trans-Retinoic Acid-Induced Proteasome Activation Potentiates the Differentiating Effect of Retinoid in Acute Myeloid Leukemia Cells
Inhibition of All-Trans-Retinoic Acid-Induced Proteasome Activation Potentiates the Differentiating Effect of Retinoid in Acute Myeloid Leukemia Cells
复制标题
抑制全反式视黄酸诱导的蛋白酶体活化增强类视黄醇在急性髓系白血病细胞中的分化作用
DOI：
10.1002/mc.20687
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发表时间：
2011-01-01
影响因子：
4.6
通讯作者：
He, Qiaojun
中科院分区：
文献类型：
--
作者：
Fang, Yanfen;Zhou, Xinglu;He, Qiaojun
全反式维甲酸(ATRA)目前被认为是白血病分化治疗的唯一有效药物；然而，ATRA的生物学作用机制在很大程度上仍不清楚。在此，我们首次报道了ATRA诱导的髓系白血病分化伴随着泛素-蛋白结合物水平的增加和蛋白酶体活性的上调。为探讨活化的蛋白酶体在维甲酸(RA)信号转导中的作用，检测了蛋白酶体抑制剂对RA诱导的细胞分化的影响。我们的结果表明，抑制ATRA升高的蛋白酶体活性明显促进了ATRA触发的髓系成熟程序，这表明过度激活的蛋白酶体不利于ATRA的作用。进一步的研究表明，ATRA和蛋白酶体抑制剂的协同分化作用可能与保护维甲酸受体α(RARα)通过泛素-蛋白酶体途径(UPP)降解有关。此外，累积的RARα能够促进其靶基因的转录，这可能也有助于促进白血病细胞的分化。总之，通过将UPP与ATRA依赖的信号联系起来，我们的数据为研究ATRA诱导的细胞效应的机制提供了新的见解，并暗示了ATRA和蛋白酶体抑制剂联合用于白血病治疗的可能性。(C)2010年Wiley-Liss公司
All-trans retinoic acid (ATRA) is nowadays considered to be the sole efficient agent for differentiation-based therapy in leukemia; however, the mechanisms of ATRA's biological effects remain largely unknown. Here we first reported that ATRA-induced myeloid leukemia differentiation was accompanied with the increased level of ubiquitin-protein conjugates and the upregulation of proteasome activity. To explore the functional role of the activated proteasome in retinoic acid (RA) signaling, the effects of proteasome inhibitors on RA-induced cell differentiation were determined. Our results demonstrated that inhibition of ATRA-elevated proteasome activity obviously promoted the myeloid maturation program triggered by ATRA, suggesting that the overactivated proteasome is not beneficial for ATRA's effects. Further studies demonstrated that the synergistic differentiating effects of ATRA and proteasome inhibitors might be associated with the protection of retinoic acid receptor alpha (RAR alpha) from degradation by the ubiquitin-proteasome pathway (UPP). Moreover, the accumulated RAR alpha was able to enhance the transcription of its target gene, which might also contribute to the enhanced differentiation of leukemia cells. Together, by linking the UPP to ATRA-dependent signaling, our data provide a novel insight into studying the mechanisms of ATRA-elicited cellular effects and imply the possibility of combination of ATRA and proteasome inhibitors in leukemia therapy. (C) 2010 Wiley-Liss, Inc.