PML-RARα enhances constitutive autophagic activity through inhibiting the Akt/mTOR pathway
PML-RARα enhances constitutive autophagic activity through inhibiting the Akt/mTOR pathway
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DOI：
10.4161/auto.7.10.16636
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发表时间：
2011-10-01
期刊：
影响因子：
13.3
通讯作者：
Chen, Guo-Qiang
中科院分区：
文献类型：
--
作者：
Huang, Ying;Hou, Jia-Kai;Chen, Guo-Qiang
自噬是一种高度保守的、受严格调控的动态平衡细胞活动，允许长寿命蛋白质和细胞质细胞器的大量降解。它在肿瘤的发生、发展和决定肿瘤细胞对抗癌治疗的反应中的作用是复杂的，对于自噬在急性髓系白血病的发病机制和治疗反应中的潜在意义的研究还很有限。在这里，我们证明了诱导或转基因表达的急性早幼粒细胞白血病(APL)特异性的PML-RARα，而不是PLZF-RARα或NPM-RARα，融合蛋白上调了白血病和非白血病细胞的结构性自噬激活，这是通过包括透射电子显微镜在内的自噬标志来评估的。在PML-RARα移植的白血病小鼠的白血病细胞浸润性骨髓和脾中也发现自噬活性显著增加。自噬抑制剂3-甲基腺嘌呤显著抑制PML-RARα上调的自噬事件，而自噬通量分析显示融合蛋白通过增加自噬隔离的开启速率而诱导自噬。此外，PML-RARα对自噬的调节可能是通过降低Akt/mTOR通路的激活来实现的。最后，我们还表明自噬有助于PML-RARα蛋白的抗凋亡功能。鉴于PML-RARA癌蛋白在APL发病机制中的关键作用，本研究提示自噬在APL的发展和治疗中具有重要作用。
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-RAR alpha, but not PLZF-RAR alpha or NPM-RAR alpha, 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-RAR alpha-transplanted leukemic mice. The autophagy inhibitor 3-methyladenine significantly abrogates the autophagic events upregulated by PML-RAR alpha, 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-RAR alpha 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-RAR alpha protein. Given the critical role of the PML-RARa oncoprotein in APL pathogenesis, this study suggests an important role of autophagy in the development and treatment of this disease.