Asparaginase induces apoptosis and cytoprotective autophagy in chronic myeloid leukemia cells.
Asparaginase induces apoptosis and cytoprotective autophagy in chronic myeloid leukemia cells.
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DOI：
10.18632/oncotarget.2869
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发表时间：
2015-02-28
期刊：
影响因子：
--
通讯作者：
Ju D
中科院分区：
文献类型：
--
作者：
Song P;Ye L;Fan J;Li Y;Zeng X;Wang Z;Wang S;Zhang G;Yang P;Cao Z;Ju D
抗肿瘤酶天冬酰胺酶以必需氨基酸l -天冬酰胺为靶点，催化生成l -天冬氨酸和氨，多年来一直用于治疗急性淋巴细胞白血病（ALL）、骨髓白血病亚型和t细胞淋巴瘤，而天冬酰胺酶抗慢性骨髓白血病（CML）的作用及其机制尚未完全阐明。我们在这里表明，天冬酰胺酶诱导K562和KU812细胞显著的生长抑制和凋亡。除了诱导细胞凋亡外，我们首次报道了天冬酰胺酶诱导K562和KU812细胞的自噬反应，包括自噬小体的形成、微管相关蛋白轻链3 （LC3）阳性的自噬样空泡的形成以及LC3- ii的上调。进一步研究表明，Akt/mTOR（哺乳动物雷帕霉素靶蛋白）和Erk（细胞外信号调节激酶）信号通路参与了天冬酰胺酶诱导的K562细胞自噬。此外，使用药物抑制剂LY294002、氯喹（CQ）和奎宁（QN）阻断自噬可增强天冬酰胺酶诱导的细胞死亡和凋亡，表明自噬在天冬酰胺酶处理的K562和KU812细胞中具有细胞保护作用。总之，这些发现提供了一个基本原理，即天冬酰胺酶抗癌活性和自噬抑制的结合可能是一种有希望的CML新治疗策略。
The antitumor enzyme asparaginase, which targets essential amino acid L-asparagine and catalyzes it to L-aspartic acid and ammonia, has been used for years in the treatment of acute lymphoblastic leukemia (ALL), subtypes of myeloid leukemia and T-cell lymphomas, whereas the anti-chronic myeloid leukemia (CML) effect of asparaginase and its underlying mechanism has not been completely elucidated. We have shown here that asparaginase induced significant growth inhibition and apoptosis in K562 and KU812 cells. Apart from induction of apoptosis, we reported for the first time that asparaginase induced autophagic response in K562 and KU812 cells as evidenced by the formation of autophagosome, microtubule-associated protein light chain 3 (LC3)-positive autophagy-like vacuoles, and the upregulation of LC3-II. Further study suggested that the Akt/mTOR (mammalian target of rapamycin) and Erk (extracellular signal-regulated kinase) signaling pathway were involved in asparaginase-induced autophagy in K562 cells. Moreover, blocking autophagy using pharmacological inhibitors LY294002, chloroquine (CQ) and quinacrine (QN) enhanced asparaginase-induced cell death and apoptosis, indicating the cytoprotective role of autophagy in asparaginase-treated K562 and KU812 cells. Together, these findings provide a rationale that combination of asparaginase anticancer activity and autophagic inhibition might be a promising new therapeutic strategy for CML.
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