Acute Mitochondrial Inhibition by Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Kinase (MEK) 1/2 Inhibitors Regulates Proliferation
Acute Mitochondrial Inhibition by Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Kinase (MEK) 1/2 Inhibitors Regulates Proliferation
复制标题
DOI：
10.1074/jbc.m112.430082
复制
发表时间：
2013-02-01
影响因子：
4.8
通讯作者：
Springett, Roger
中科院分区：
文献类型：
--
作者：
Ripple, Maureen O.;Kim, Namjoon;Springett, Roger
Ras-MEK1/2-ERK1/2激酶信号通路调节增殖、存活和分化，由于它在肿瘤中经常是异常的，因此是小分子抑制的热门靶点。一项新的代谢分析测量了完整活细胞内NAD(H)和电子传递链血红素的实时氧化状态和氧消耗，发现结构不同的MEK1/2抑制剂对线粒体代谢具有直接的剂量依赖性作用。抑制剂U0126、MIIC和PD98059导致NAD(H)还原、血红素氧化和氧气消耗降低，具有复合物I抑制的特征。PD198306是一种口服活性MEK1/2抑制剂，起到解偶联剂的作用。每种MEK1/2抑制剂都能减少磷酸化的ERK1/2并抑制增殖，但最强大的抗增殖作用总是与线粒体抑制而不是MEK1/2抑制后的代谢衰竭相关。这需要重新思考ERK1/2在增殖中的作用，并强调线粒体功能在这一过程中的重要性。
The Ras-MEK1/2-ERK1/2 kinase signaling pathway regulates proliferation, survival, and differentiation and, because it is often aberrant in tumors, is a popular target for small molecule inhibition. A novel metabolic analysis that measures the real-time oxidation state of NAD(H) and the hemes of the electron transport chain and oxygen consumption within intact, living cells found that structurally distinct MEK1/2 inhibitors had an immediate, dose-dependent effect on mitochondrial metabolism. The inhibitors U0126, MIIC and PD98059 caused NAD(H) reduction, heme oxidation, and decreased oxygen consumption, characteristic of complex I inhibition. PD198306, an orally active MEK1/2 inhibitor, acted as an uncoupler. Each MEK1/2 inhibitor depleted phosphorylated ERK1/2 and inhibited proliferation, but the most robust antiproliferative effects always correlated with the metabolic failure which followed mitochondrial inhibition rather than inhibition of MEK1/2. This warrants rethinking the role of ERK1/2 in proliferation and emphasizes the importance of mitochondrial function in this process.