Autophagy 2011 Oct;7 (10): 1132-44. [IF:6.643]
PML-RARα enhances constitutive autophagic activity through inhibiting the Akt/mTOR pathway.
Huang Y , Hou JK , Chen TT , Zhao XY , Yan ZW , Zhang J , Yang J , Kogan SC , Chen GQ .
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
上海交通大学药学院，细胞分化与凋亡教育部重点实验室
Abstract
Autophagy is a highly conserved, closely regulated homeostatic cellular activity that allows for the bulk degradation of long-lived proteins and cytoplasmic organelles. Its roles in cancer initiation and progression and in determining the response of tumor cells to anticancer therapy are complicated, and only limited investigation has been conducted on the potential significance of autophagy in the pathogenesis and therapeutic response of acute myeloid leukemia. Here we demonstrate that the inducible or transfected expression of the acute promyelocytic leukemia (APL)-specific PML-RARα, but not PLZF-RARα or NPM-RARα, fusion protein upregulates constitutive autophagy activation in leukemic and nonleukemic cells, as evaluated by hallmarks for autophagy including transmission electron microscopy. The significant increase in autophagic activity is also found in the leukemic cells-infiltrated bone marrow and spleen from PML-RARα-transplanted leukemic mice. The autophagy inhibitor 3-methyladenine significantly abrogates the autophagic events upregulated by PML-RARα, while the autophagic flux assay reveals that the fusion protein induces autophagy by increasing the on-rate of autophagic sequestration. Furthermore, this modulation of autophagy by PML-RARα is possibly mediated by a decreased activation of the Akt/mTOR pathway. Finally, we also show that autophagy contributes to the anti-apoptotic function of the PML-RARα protein. Given the critical role of the PML-RARα oncoprotein in APL pathogenesis, this study suggests an important role of autophagy in the development and treatment of this disease.
摘要
自我吞噬一种相当保守的，非常有序的自我调节的细胞活动，这种活动会容许细胞内的长时间存在的蛋白和胞质细胞器降解以维持胞内平衡。自我吞噬在癌症的发生与发展以及靶细胞对抗癌治疗的应答的决定上所扮演的角色是非常复杂的，并且仅有少数的研究指明自我吞噬作用在急性骨髓性白血病的发病机理和治疗应答上有潜在重要性。正像从电子透射显微镜（tem）等细胞标记所观察到的自我吞噬现象，我们推论，特别是PML-RARα蛋白（而不是PLZF-RARα 和 NPM-RARα）在急性前骨髓细胞癌白血病（APL）被诱导或者转染的表达过程中，提高了在白血病和非白血病细胞的自我吞噬作用。这中自我吞噬能力的增强在转染了PML-RARα基因的携带白血病小鼠的白血病细胞渗透的骨髓和脾脏中也被发现。自我免疫抑制剂3-甲基腺嘌呤能够有效的终止PML-RA介导的自我免疫反应，通过自噬检测揭示PML-RA融合蛋白通过增加自噬隔离的速度来诱导自我免疫。而且，PML-RARα对自我吞噬的调节可能会被Akt/mTOR途径的激活所终止。最后，我们也指出，自我吞噬作用归功于抗凋亡的PML-RARα p蛋白。如果给PML-RARα肿瘤蛋白在急性前骨髓细胞癌白血病中一个严格的定性，那么我们觉得它在PML-RARα发展和APL疾病的处理的自我免疫之间扮演了一个重要的角色。
