Tumour maintenance is mediated by eNOS
Tumour maintenance is mediated by eNOS
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DOI：
10.1038/nature06778
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发表时间：
2008-04-03
期刊：
影响因子：
64.8
通讯作者：
Counter, Christopher M.
中科院分区：
文献类型：
--
作者：
Lim, Kian-Huat;Ancrile, Brooke B.;Counter, Christopher M.
肿瘤细胞对起始癌基因（如Ras）的表达上瘾，因此在已建立的肿瘤中癌基因表达的丧失导致肿瘤消退（1）。在许多癌症中，HRas、NRas或KRas突变以保持活性GTP结合致癌状态（2）。尽管Ras激活几种蛋白质以启动人类肿瘤生长，但只有PI 3 K通过激活蛋白激酶B（PK B;也称为AKT）必须保持被致癌Ras激活以维持这种生长63。在这里，我们表明，阻断磷酸化的AKT底物，内皮型一氧化氮合酶（eNOS或NOS 3），抑制肿瘤的发生和维持。此外，eNOS增强了在整个肿瘤发生过程中所需的内源性野生型Ras蛋白的亚硝基化和活化。我们认为癌细胞中致癌Ras激活PI 3 K-AKT- eNOS -（野生型）Ras通路是启动和维持肿瘤生长所必需的.
Tumour cells become addicted to the expression of initiating oncogenes like Ras, such that loss of oncogene expression in established tumours leads to tumour regression(1). HRas, NRas or KRas are mutated to remain in the active GTP- bound oncogenic state in many cancers(2). Although Ras activates several proteins to initiate human tumour growth, only PI3K, through activation of protein kinase B ( PKB; also known as AKT), must remain activated by oncogenic Ras to maintain this growth63. Here we show that blocking phosphorylation of the AKT substrate, endothelial nitric oxide synthase ( eNOS or NOS3), inhibits tumour initiation and maintenance. Moreover, eNOS enhances the nitrosylation and activation of endogenous wild- type Ras proteins, which are required throughout tumorigenesis. We suggest that activation of the PI3K - AKT - eNOS -( wild- type) Ras pathway by oncogenic Ras in cancer cells is required to initiate and maintain tumour growth.