Activation of a novel calcineurin-mediated insulin-like growth factor-1 receptor pathway, altered metabolism, and tumor cell invasion in cells subjected to mitochondrial respiratory stress
Activation of a novel calcineurin-mediated insulin-like growth factor-1 receptor pathway, altered metabolism, and tumor cell invasion in cells subjected to mitochondrial respiratory stress
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DOI：
10.1074/jbc.m611693200
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发表时间：
2007-05-11
影响因子：
4.8
通讯作者：
Avadhani, Narayan G.
中科院分区：
文献类型：
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作者：
Guha, Manti;Srinivasan, Satish;Avadhani, Narayan G.
我们以前已经表明，线粒体膜电位的破坏，耗尽的线粒体DNA（mtDNA）或处理与线粒体离子载体，羰基氰间氯苯腙，启动应激信号，这导致抗凋亡，并诱导侵入行为在C2 C12心肌细胞和A549细胞。在本研究中，我们发现，钙调神经磷酸酶（Cn），激活作为这种应激信号的一部分，在增加葡萄糖摄取和糖酵解中起着重要作用。在这里，我们报告说，虽然胰岛素和胰岛素样生长因子-1受体水平（IR和IGF 1 R，分别）增加线粒体应激，IGF 1 R的自磷酸化选择性增加，表明受体途径的转变。使用FK 506（一种Cn抑制剂）和通过小干扰RNA进行mRNA沉默的方法，我们表明线粒体应激激活的Cn对GLUT 4和IGF 1 R表达和激活的增加至关重要。IGF 1 R途径在线粒体应激下细胞存活中的重要性通过IGF 1 R mRNA沉默或IGF 1 R抑制剂（AG 1024和苦鬼臼脂素）处理增加的细胞凋亡来证明。这项研究描述了一种新的机制，线粒体应激诱导的代谢转变涉及Cn与抗凋亡和肿瘤增殖的影响。
We have previously shown that disruption of mitochondrial membrane potential by depletion of mitochondrial DNA ( mtDNA) or treatment with a mitochondrial ionophore, carbonyl cyanide m-chlorophenylhydrazone, initiates a stress signaling, which causes resistance to apoptosis, and induces invasive behavior in C2C12 myocytes and A549 cells. In the present study we show that calcineurin (Cn), activated as part of this stress signaling, plays an important role in increased glucose uptake and glycolysis. Here we report that, although both insulin and insulin-like growth factor-1 receptor levels (IR and IGF1R, respectively) are increased in response to mitochondrial stress, autophosphorylation of IGF1R was selectively increased suggesting a shift in receptor pathways. Using an approach with FK506, an inhibitor of Cn, and mRNA silencing by small interference RNA we show that mitochondrial stress-activated Cn is critical for increased GLUT 4 and IGF1R expression and activation. The importance of the IGF1R pathway in cell survival under mitochondrial stress is demonstrated by increased apoptosis either by IGF1R mRNA silencing or by treatment with IGF1R inhibitors (AG1024 and picropodophyllin). This study describes a novel mechanism of mitochondrial stress-induced metabolic shift involving Cn with implications in resistance to apoptosis and tumor proliferation.