A critical role of autophagy in antileukemia/lymphoma effects of APO866, an inhibitor of NAD biosynthesis
A critical role of autophagy in antileukemia/lymphoma effects of APO866, an inhibitor of NAD biosynthesis
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DOI：
10.4161/auto.27722
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发表时间：
2014-04-01
期刊：
影响因子：
13.3
通讯作者：
Nahimana, Aimable
中科院分区：
文献类型：
--
作者：
Ginet, Vanessa;Puyal, Julien;Nahimana, Aimable
APO866是一种NAD生物合成抑制剂，在多种恶性肿瘤中显示出强大的抗肿瘤特性。近年来，研究发现APO866可诱导人血液癌细胞发生凋亡和自噬，但自噬在APO866诱导的细胞死亡中的作用尚不清楚。在这里，我们报告了APO866诱导细胞死亡的分子机制的研究，重点是自噬。APO866处理白血病和淋巴瘤细胞不仅诱导了自噬，表现为自噬小体的形成和SQSTM1/p62降解的增加，而且还增加了caspase的激活，表现为CASP3/caspase 3的裂解。作为一种潜在的机制，APO866介导的自噬被发现耗尽了活性氧(ROS)清除剂CAT/CAT酶，从而促进了ROS的产生和细胞死亡。ATG5或ATG7沉默抑制自噬可阻止CAT降解、ROS产生、caspase激活和APO866诱导的细胞死亡。添加外源CAT后，APO866细胞毒活性也随之降低。总之，我们的结果表明，自噬是APO866对血液系统恶性肿瘤细胞的细胞毒活性所必需的，也表明了自噬依赖的CAT降解，这是APO866介导的细胞杀伤的一种新机制。自噬调控可能成为增强APO866及其相关药物抗肿瘤活性的新途径。
APO866, an inhibitor of NAD biosynthesis, exhibits potent antitumor properties in various malignancies. Recently, it has been shown that APO866 induces apoptosis and autophagy in human hematological cancer cells, but the role of autophagy in APO866-induced cell death remains unclear. Here, we report studies on the molecular mechanisms underlying APO866-induced cell death with emphasis on autophagy. Treatment of leukemia and lymphoma cells with APO866 induced both autophagy, as evidenced by an increase in autophagosome formation and in SQSTM1/p62 degradation, but also increased caspase activation as revealed by CASP3/caspase 3 cleavage. As an underlying mechanism, APO866-mediated autophagy was found to deplete CAT/catalase, a reactive oxygen species (ROS) scavenger, thus promoting ROS production and cell death. Inhibition of autophagy by ATG5 or ATG7 silencing prevented CAT degradation, ROS production, caspase activation, and APO866-induced cell death. Finally, supplementation with exogenous CAT also abolished APO866 cytotoxic activity. Altogether, our results indicated that autophagy is essential for APO866 cytotoxic activity on cells from hematological malignancies and also indicate an autophagy-dependent CAT degradation, a novel mechanism for APO866-mediated cell killing. Autophagy-modulating approaches could be a new way to enhance the antitumor activity of APO866 and related agents.