Cytoprotective effect of the elongation factor-2 kinase-mediated autophagy in breast cancer cells subjected to growth factor inhibition.
Cytoprotective effect of the elongation factor-2 kinase-mediated autophagy in breast cancer cells subjected to growth factor inhibition.
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DOI：
10.1371/journal.pone.0009715
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发表时间：
2010-03-16
期刊：
影响因子：
3.7
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
Cheng Y;Li H;Ren X;Niu T;Hait WN;Yang J
自噬是一种高度保守和受调控的细胞过程，由活细胞降解蛋白质和细胞器作为对代谢应激的反应。我们以前报道过真核细胞延伸因子-2激酶（eEF-2 kinase，也称为Ca 2 +/钙调素依赖性蛋白激酶III）可以正向调节自噬和负向调节蛋白质合成。本研究的目的是确定eEF-2激酶调节的自噬在乳腺癌细胞对生长因子信号传导抑制剂的反应中的作用。我们发现，营养耗尽或生长因子抑制剂激活人乳腺癌细胞中的自噬，并且自噬活性的增加与细胞ATP的减少以及AMP激酶和eEF-2激酶活性的增加相关。eEF-2激酶的沉默解除了蛋白质合成的抑制，导致细胞ATP的更大减少，并减弱自噬反应。我们进一步表明，抑制eEF-2激酶调节的自噬阻碍了血清/营养缺乏培养物中的细胞生长，阻碍了细胞存活，并增强了生长因子抑制剂如曲妥珠单抗、吉非替尼和拉帕替尼的疗效。这项研究的结果提供了新的证据，表明eEF-2激酶介导的自噬激活在代谢应激条件下对癌细胞起保护作用，并且靶向自噬存活可能代表了增强生长因子抑制剂有效性的新方法。
Autophagy is a highly conserved and regulated cellular process employed by living cells to degrade proteins and organelles as a response to metabolic stress. We have previously reported that eukaryotic elongation factor-2 kinase (eEF-2 kinase, also known as Ca2+/calmodulin-dependent protein kinase III) can positively modulate autophagy and negatively regulate protein synthesis. The purpose of the current study was to determine the role of the eEF-2 kinase-regulated autophagy in the response of breast cancer cells to inhibitors of growth factor signaling. We found that nutrient depletion or growth factor inhibitors activated autophagy in human breast cancer cells, and the increased activity of autophagy was associated with a decrease in cellular ATP and an increase in activities of AMP kinase and eEF-2 kinase. Silencing of eEF-2 kinase relieved the inhibition of protein synthesis, led to a greater reduction of cellular ATP, and blunted autophagic response. We further showed that suppression of eEF-2 kinase-regulated autophagy impeded cell growth in serum/nutrient-deprived cultures and handicapped cell survival, and enhanced the efficacy of the growth factor inhibitors such as trastuzumab, gefitinib, and lapatinib. The results of this study provide new evidence that activation of eEF-2 kinase-mediated autophagy plays a protective role for cancer cells under metabolic stress conditions, and that targeting autophagic survival may represent a novel approach to enhancing the effectiveness of growth factor inhibitors.
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影响因子：
13.3
作者：
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通讯作者：
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影响因子：
45.3
作者：
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DOI：
10.1073/pnas.0408345102
发表时间：
2004-12-28
影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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