The anticancer effects of pharmacological inhibition of autophagy in acute erythroid leukemia cells
The anticancer effects of pharmacological inhibition of autophagy in acute erythroid leukemia cells
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DOI：
10.1097/cad.0000000000000668
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发表时间：
2018-11-01
影响因子：
2.3
通讯作者：
Atashi, Amir
中科院分区：
文献类型：
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作者：
Kazemi, Alireza;Sadri, Mohammadreza;Atashi, Amir
尽管最近的研究报道了自噬的不同方面，从该过程在恶性细胞中的促生存到促死亡的作用，但自噬抑制剂有助于诱导癌细胞程序性细胞死亡的潜在机制仍不清楚。在本研究中，我们试图探索 TF-1 细胞（急性红系白血病模型）自噬的药理学抑制的一些分子特征。我们的研究结果表明，ara-C 会诱导细胞自噬（伴随 LC3B、p62 和 Beclin-1 的改变）；然而，通过 3-甲基腺嘌呤和氯喹靶向自噬显着增加了 ara-C 处理的细胞中 caspase 依赖性细胞凋亡和亚 G(1) 区室。此外，细胞周期分析表明，3-MA作为早期自噬抑制剂，可以提高细胞周期G(0)/G(1)期的细胞群，这与p21和p27表达上调有关。有趣的是，自噬抑制还伴随着 c-Myc 基因和蛋白表达水平的下调以及 Bax 和 Bak 基因表达水平的上调。此外，抑制自噬后，肿瘤抑制 miRNA（即 miR-204）的水平升高，而致癌 miRNA（包括 miR-21、miR-221、miR-30a 和 miR-17）的值降低。总的来说，我们的实验表明自噬抑制剂（尤其是氯喹）似乎是急性红细胞白血病联合治疗的有前途的药物。版权所有 (C) 2018 Wolters Kluwer Health, Inc. 保留所有权利。
Although recent studies have reported different aspects of autophagy, from pro-survival to pro-death roles of this process in malignant cells, the underlying mechanisms by which autophagy inhibitors contribute toward the induction of programmed cell death in cancerous cells are still unclear. In the present study, we have attempted to explore some of the molecular features of pharmacological inhibition of autophagy in TF-1 cells (an acute erythroid leukemia model). Our findings indicated that ara-C induces autophagy (with alteration of LC3B, p62, and Beclin-1) in the cells; however, targeting autophagy by 3-methyladenine and chloroquine significantly increased caspase-dependent apoptosis and the sub-G(1) compartment in ara-C-treated cells. Moreover, cell cycle analysis showed that 3-MA, as an early-stage autophagy inhibitor, could elevate the cell population in the G(0)/G(1) cell cycle phase, which was associated with upregulation of p21 and p27 expressions. Interestingly, autophagy inhibition was also accompanied by downregulation of c-Myc gene and protein expression levels and upregulated levels of Bax and Bak gene expressions. In addition, following inhibition of autophagy, the levels of tumor-suppressive miRNA (i.e. miR-204) increased, whereas the values of oncogenic miRNAs (including miR-21, miR-221, miR-30a, and miR-17) decreased. Overall, our experiments indicate that autophagy inhibitors (especially chloroquine) seem to be promising agents for combination therapy in acute erythroid leukemia. Copyright (C) 2018 Wolters Kluwer Health, Inc. All rights reserved.