Lim Kian-Huat, Ancrile Brooke B, Kashatus David F, Counter Christopher M
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Nature. 2008 Apr 3;452(7187):646-9. doi: 10.1038/nature06778. Epub 2008 Mar 16.
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. HRas, NRas or KRas are mutated to remain in the active GTP-bound oncogenic state in many cancers. 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 growth. 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.
肿瘤细胞会对启动癌基因（如Ras）的表达产生依赖，以至于在已形成的肿瘤中癌基因表达缺失会导致肿瘤消退。在许多癌症中，HRas、NRas或KRas发生突变以保持处于活性GTP结合的致癌状态。虽然Ras激活多种蛋白质以启动人类肿瘤生长，但只有磷脂酰肌醇-3-激酶（PI3K）通过激活蛋白激酶B（PKB，也称为AKT），必须被致癌性Ras持续激活才能维持这种生长。我们在此表明，阻断AKT底物内皮型一氧化氮合酶（eNOS或NOS3）的磷酸化可抑制肿瘤起始和维持。此外，eNOS增强内源性野生型Ras蛋白的亚硝基化和激活，这在整个肿瘤发生过程中都是必需的。我们认为，癌细胞中致癌性Ras对PI3K-AKT-eNOS-（野生型）Ras途径的激活是启动和维持肿瘤生长所必需的。
