Docosahexaenoic acid induces autophagy through p53/AMPK/mTOR signaling and promotes apoptosis in human cancer cells harboring wild-type p53
Docosahexaenoic acid induces autophagy through p53/AMPK/mTOR signaling and promotes apoptosis in human cancer cells harboring wild-type p53
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DOI：
10.4161/auto.7.11.16658
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发表时间：
2011-11-01
期刊：
影响因子：
13.3
通讯作者：
Lim, Kyu
中科院分区：
文献类型：
--
作者：
Jing, Kaipeng;Song, Kyoung-Sub;Lim, Kyu
二十二碳六烯酸（DHA）有诱导肿瘤细胞凋亡的报道。然而，人们对DHA对自噬的影响知之甚少，自噬是另一个复杂的程序良好的过程，其特征是自噬体内细胞质物质的隔离。本研究表明，DHA增加了微管相关蛋白1轻链3的水平和自噬泡的数量，但不损害自噬泡的更新，表明DHA不仅诱导细胞凋亡，还诱导自噬。我们还观察到dha诱导的自噬伴随着p53的丢失。抑制p53可增加dha诱导的自噬，抑制p53降解可显著减弱dha诱导的自噬，提示dha诱导的自噬是由p53介导的。进一步的实验表明，dha诱导的自噬与p53衰减相关的机制涉及amp激活的蛋白激酶活性形式的增加和哺乳动物雷帕霉素靶蛋白活性的降低。此外，DHA诱导的自噬与凋亡之间的相互作用也得到了有力证据的支持，自噬抑制抑制了细胞凋亡，进一步的自噬诱导在DHA处理后增强了细胞凋亡。总的来说，我们的研究结果表明，自噬有助于DHA对携带野生型p53的癌细胞的细胞毒性。
Docosahexaenoic acid (DHA) has been reported to induce tumor cell death by apoptosis. However, little is known about the effects of DHA on autophagy, another complex well-programmed process characterized by the sequestration of cytoplasmic material within autophagosomes. Here we show that DHA increased both the level of microtubule-associated protein 1 light chain 3 and the number of autophagic vacuoles without impairing autophagic vesicle turnover, indicating that DHA induces not only apoptosis but also autophagy. We also observed that DHA-induced autophagy was accompanied by p53 loss. Inhibition of p53 increased DHA-induced autophagy and prevention of p53 degradation significantly led to the attenuation of DHA-induced autophagy, suggesting that DHA-induced autophagy is mediated by p53. Further experiments showed that the mechanism of DHA-induced autophagy associated with p53 attenuation involved an increase in the active form of AMP-activated protein kinase and a decrease in the activity of mammalian target of rapamycin. In addition, compelling evidence for the interplay between autophagy and apoptosis induced by DHA is supported by the findings that autophagy inhibition suppressed apoptosis and further autophagy induction enhanced apoptosis in response to DHA treatment. Overall, our results demonstrate that autophagy contributes to the cytotoxicity of DHA in cancer cells harboring wild-type p53.