NOS1 S-nitrosylates PTEN and inhibits autophagy in nasopharyngeal carcinoma cells.
NOS1 S-nitrosylates PTEN and inhibits autophagy in nasopharyngeal carcinoma cells.
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NOS1 S-亚硝基化 PTEN 并抑制鼻咽癌细胞的自噬。
DOI：
10.1038/cddiscovery.2017.11
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发表时间：
2017
影响因子：
7
通讯作者：
Liu Q
中科院分区：
文献类型：
--
作者：
Zhu L;Li L;Zhang Q;Yang X;Zou Z;Hao B;Marincola FM;Liu Z;Zhong Z;Wang M;Li X;Wang Q;Li K;Gao W;Yao K;Liu Q
自噬是一种细胞生存机制，涉及代谢应激期间受损蛋白质和细胞器的分解代谢降解，并且当过度刺激时，通常导致细胞死亡。一氧化氮（NO）是一种有效的细胞信使，参与了一种复杂的机制，有助于控制自噬。然而，内源性NO形成的不同亚型的一氧化氮合酶（NOS）有助于调节癌细胞中的自噬的机制仍然不清楚。在这里，我们报告说，NOS 1减少过度的自噬水平，促进鼻咽癌细胞的生存。我们发现，抑制NOS 1增加了siRNA或使用药物引起的细胞死亡;这种作用被自噬抑制剂氯喹逆转。NOS 1在自噬过程中的作用依赖于磷酸酶和张力蛋白同源物（PTEN）蛋白的S-亚硝基化激活AKT/mTOR信号传导。NOS 1修饰PTEN蛋白的机制可能涉及这两种分子之间的直接相互作用。此外，在体内研究中，NOS 1抑制剂N（G）-硝基-L-精氨酸甲酯激活AKT/mTOR信号传导并促进异种移植肿瘤中的自噬。我们的研究表明，NOS 1通过PTEN的S-亚硝基化和AKT/mTOR信号通路的激活来防止过度的自噬。PTEN和AKT/mTOR信号通路是改善癌症化疗治疗的有希望的靶点。
Autophagy is a cellular survival mechanism that involves the catabolic degradation of damaged proteins and organelles during periods of metabolic stress, and when overly stimulated, commonly contributes to cell death. Nitric oxide (NO), a potent cellular messenger, participates in a complex mechanism which assists in controlling autophagy. However, the mechanism by which endogenous NO formed by distinct isoforms of nitric oxide synthase (NOS) helps to regulate autophagy in cancer cells remains unclear. Here we report that NOS1 reduces excessive levels of autophagy and promotes the survival of nasopharyngeal carcinoma cells. We found that inhibition of NOS1 increased cell death resulting from siRNA or the use of pharmacologic agents; and this effect was reversed by the autophagy inhibitor, chloroquine. The role of NOS1 in the autophagy process depended on the activation of AKT/mTOR signaling by S-nitrosylation of phosphatase and tensin homolog (PTEN) proteins. The mechanism by which NOS1 modifies PTEN protein might involve a direct interaction between these two molecules. Moreover, in an in vivo study, the NOS1 inhibitor N(G)-nitro-L-arginine methyl ester activated AKT/mTOR signaling and promoted autophagy in xenograph tumors. Our studies demonstrated that NOS1 prevents excessive autophagy via S-nitrosylation of PTEN, and activation of the AKT/mTOR signaling pathway. PTEN and the AKT/mTOR signaling pathway are promising targets for improving the chemotherapeutic treatment of cancer.