Phospholipase D2 Mediates Survival Signaling through Direct Regulation of Akt in Glioblastoma Cells
Phospholipase D2 Mediates Survival Signaling through Direct Regulation of Akt in Glioblastoma Cells
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DOI：
10.1074/jbc.m113.532978
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发表时间：
2014-01-10
影响因子：
4.8
通讯作者：
Brown, H. Alex
中科院分区：
文献类型：
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作者：
Bruntz, Ronald C.;Taylor, Harry E.;Brown, H. Alex
多形性胶质母细胞瘤（GBM）缺乏创新药物靶点，这使得患者在确诊后的生存期大约限制在1年。促生存激酶Akt为GBM的治疗提供了一个理想靶点，因为Akt信号通路在这种癌症类型中经常被激活。然而，Akt在生理过程中的核心作用限制了它作为治疗靶点的潜力。在本报告中，我们表明脂质代谢酶磷脂酶D（PLD）是GBM中Akt的一种新型调节因子。结合使用小分子PLD抑制剂和小干扰RNA敲低的研究确定，PLD反应的产物磷脂酸是Akt膜募集和激活的关键成分。抑制PLD酶活性以及随后的Akt激活通过特异性抑制自噬通量降低了GBM细胞的活力。我们提出一种机制，即Akt对beclin1的磷酸化阻止了Rubicon（含RUN结构域富含半胱氨酸结构域的beclin1相互作用蛋白）的结合，已知这种相互作用会抑制自噬通量。这些发现提供了一个新的框架，通过该框架可以在不直接针对激酶的情况下实现对Akt的抑制。
The lack of innovative drug targets for glioblastoma multiforme (GBM) limits patient survival to approximately 1 year following diagnosis. The pro-survival kinase Akt provides an ideal target for the treatment of GBM as Akt signaling is frequently activated in this cancer type. However, the central role of Akt in physiological processes limits its potential as a therapeutic target. In this report, we show that the lipid-metabolizing enzyme phospholipase D (PLD) is a novel regulator of Akt in GBM. Studies using a combination of small molecule PLD inhibitors and siRNA knockdowns establish phosphatidic acid, the product of the PLD reaction, as an essential component for the membrane recruitment and activation of Akt. Inhibition of PLD enzymatic activity and subsequent Akt activation decreases GBM cell viability by specifically inhibiting autophagic flux. We propose a mechanism whereby phosphorylation of beclin1 by Akt prevents binding of Rubicon (RUN domain cysteine-rich domain containing beclin1-interacting protein), an interaction known to inhibit autophagic flux. These findings provide a novel framework through which Akt inhibition can be achieved without directly targeting the kinase.