AMPK-ULK1-Mediated Autophagy Confers Resistance to BET Inhibitor JQ1 in Acute Myeloid Leukemia Stem Cells
AMPK-ULK1-Mediated Autophagy Confers Resistance to BET Inhibitor JQ1 in Acute Myeloid Leukemia Stem Cells
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DOI：
10.1158/1078-0432.ccr-16-1903
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发表时间：
2017-06-01
影响因子：
11.5
通讯作者：
Min, Yoo Hong
中科院分区：
文献类型：
--
作者：
Jang, Ji Eun;Eom, Ju-In;Min, Yoo Hong
目的：溴结构域和末端外结构域（BET）抑制剂是用于治疗急性髓性白血病（AML）的各种亚群的有希望的表观遗传剂。然而，白血病干细胞（LSC）对BET抑制剂的耐药性仍然是一个重大挑战。在这项研究中，我们评估了LSC对BET抑制剂JQ 1的耐药性的机制。实验设计：我们评估了JQ 1诱导的LSC样白血病细胞系和原发性CD 34（+）CD 38（-）白血病母细胞中的凋亡和自噬水平，这些白血病母细胞来自于具有正常核型且无复发突变的AML病例。JQ 1在JQ 1敏感的AML细胞中以浓度依赖性方式有效地诱导凋亡。然而，在JQ 1耐药的AML LSC中，JQ 1几乎不诱导细胞凋亡，并导致beclin-1上调，LC 3-II脂化增加，自噬体形成和p62/SQSTM 1下调。通过药物抑制剂抑制自噬或使用特异性siRNA敲低beclin-1增强了JQ 1诱导的耐药细胞凋亡，表明这些细胞中发生了促生存自噬。独立于mTOR信号传导，AMPK（pThr 172）/ULK 1（pSer 555）通路的激活被发现与抗性细胞中JQ 1诱导的自噬相关。AMPK抑制使用药物抑制剂化合物C或通过敲低AMPK α抑制自噬和促进JQ 1诱导的AML LSCs.Conclusions凋亡：这些研究结果表明，促生存自噬是AML LSC对JQ 1耐药的机制之一。靶向AMPK/ULK 1通路或抑制自噬可能是对抗AML和其他类型癌症对BET抑制剂耐药性的有效治疗策略。(C)2016年AACR。
Purpose: Bromodomain and extraterminal domain (BET) inhibitors are promising epigenetic agents for the treatment of various subsets of acute myeloid leukemia (AML). However, the resistance of leukemia stem cells (LSC) to BET inhibitors remains a major challenge. In this study, we evaluated the mechanisms underlying LSC resistance to the BET inhibitor JQ1.Experimental Design: We evaluated the levels of apoptosis and autophagy induced by JQ1 in LSC-like leukemia cell lines and primary CD34(+)CD38(-) leukemic blasts obtained from AML cases with normal karyotype without recurrent mutations.Results: JQ1 effectively induced apoptosis in a concentration-dependent manner in JQ1-sensitive AML cells. However, in JQ1-resistant AML LSCs, JQ1 induced little apoptosis and led to upregulation of beclin-1, increased LC3-II lipidation, formation of autophagosomes, and downregulation of p62/SQSTM1. Inhibition of autophagy by pharmacologic inhibitors or knockdown of beclin-1 using specific siRNA enhanced JQ1-induced apoptosis in resistant cells, indicating that prosurvival autophagy occurred in these cells. Independent of mTOR signaling, activation of the AMPK (pThr172)/ULK1 (pSer555) pathway was found to be associated with JQ1-induced autophagy in resistant cells. AMPK inhibition using the pharmacologic inhibitor compound C or by knockdown of AMPK alpha suppressed autophagy and promoted JQ1-induced apoptosis in AML LSCs.Conclusions: These findings revealed that prosurvival autophagy was one of the mechanisms involved in the resistance AML LSCs to JQ1. Targeting the AMPK/ULK1 pathway or inhibition of autophagy could be an effective therapeutic strategy for combating resistance to BET inhibitors in AML and other types of cancer. (C) 2016 AACR.