Department of Molecular Medicine, National Institute of Genetic Engineering and Biotechnology, Tehran 14965/161, Iran.
Equipe labellisée par la Ligue contre le cancer, Université Paris Descartes, Université Sorbonne Paris Cité, Université Paris Diderot, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Paris 75006, France.
Int J Mol Sci. 2019 Jul 20;20(14):3559. doi: 10.3390/ijms20143559.
Autophagy is one of the main cellular catabolic pathways controlling a variety of physiological processes, including those involved in self-renewal, differentiation and death. While acute promyelocytic leukemia (APL) cells manifest low levels of expression of autophagy genes associated with reduced autophagy activity, the introduction of all- retinoid acid (ATRA)-a differentiating agent currently used in clinical settings-restores autophagy in these cells. ATRA-induced autophagy is involved in granulocytes differentiation through a mechanism that involves among others the degradation of the PML-RARα oncoprotein. Arsenic trioxide (ATO) is another anti-cancer agent that promotes autophagy-dependent clearance of promyelocytic leukemia retinoic acid receptor alpha gene (PML-RARα) in APL cells. Hence, enhancing autophagy may have therapeutic benefits in maturation-resistant APL cells. However, the role of autophagy in response to APL therapy is not so simple, because some autophagy proteins have been shown to play a pro-survival role upon ATRA and ATO treatment, and both agents can activate ETosis, a type of cell death mediated by the release of neutrophil extracellular traps (ETs). This review highlights recent findings on the impact of autophagy on the mechanisms of action of ATRA and ATO in APL cells. We also discuss the potential role of autophagy in the development of resistance to treatment, and of differentiation syndrome in APL.
自噬是控制多种生理过程的主要细胞分解代谢途径之一，包括自我更新、分化和死亡。虽然急性早幼粒细胞白血病 (APL) 细胞表现出与自噬活性降低相关的自噬基因表达水平低，但全反式维甲酸 (ATRA)-一种目前用于临床的分化剂的引入可恢复这些细胞中的自噬。ATRA 诱导的自噬通过涉及降解 PML-RARα 癌蛋白等机制参与粒细胞分化。三氧化二砷 (ATO) 是另一种抗癌剂，可促进 APL 细胞中依赖自噬的早幼粒细胞白血病维甲酸受体 alpha 基因 (PML-RARα) 的清除。因此，增强自噬可能对成熟抵抗的 APL 细胞具有治疗益处。然而，自噬在 APL 治疗中的作用并不那么简单，因为一些自噬蛋白已被证明在 ATRA 和 ATO 治疗中发挥促生存作用，并且这两种药物都可以激活 ETosis，这是一种由中性粒细胞胞外陷阱 (ET) 释放介导的细胞死亡类型。本综述强调了自噬对 ATRA 和 ATO 在 APL 细胞中的作用机制的影响的最新发现。我们还讨论了自噬在治疗耐药性发展和 APL 分化综合征中的潜在作用。
