S-Nitrosylation in endothelial cells contributes to tumor cell adhesion and extravasation during breast cancer metastasis.
S-Nitrosylation in endothelial cells contributes to tumor cell adhesion and extravasation during breast cancer metastasis.
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内皮细胞中的S-亚硝基化有助于乳腺癌转移期间肿瘤细胞粘附和渗出。
DOI：
10.1186/s40659-023-00461-2
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发表时间：
2023-09-29
影响因子：
6.7
通讯作者：
Sanchez FA
中科院分区：
文献类型：
--
作者：
Koning T;Cordova F;Aguilar G;Sarmiento J;Mardones GA;Boric M;Varas-Godoy M;Lladser A;Duran WN;Ehrenfeld P;Sanchez FA
一氧化氮是由不同的一氧化氮合酶异构体产生的。NO激活两个信号通路，一个依赖于可溶性鸟苷酸环化酶和蛋白激酶G，另一个是NO在翻译后通过s -亚硝基化修饰蛋白质，这是NO对蛋白质中游离巯基半胱氨酸的修饰，形成s -亚硝基硫醇。乳腺癌患者血液中检测到高水平的NO，侵袭性乳腺肿瘤中NOS活性较良性或正常乳腺组织升高，提示NO生物合成与恶性程度及转移呈正相关。在转移过程中，内皮细胞发挥关键作用，使肿瘤细胞粘附，这是外渗过程中导致转移的第一步。这一步骤与白细胞粘附内皮细胞有相似之处，似乎也可能有一些共同的调控因素。内皮细胞表面表达的血管细胞粘附分子-1 （vascular cell adhesion molecule-1, VCAM-1）促进内皮细胞与肿瘤细胞及白细胞之间的相互作用。数据显示，乳腺肿瘤细胞粘附在血管中一氧化氮生成增加的区域，然而，其机制尚不清楚。我们报道了用来自乳腺肿瘤细胞的白细胞介素-8和条件培养基刺激内皮细胞，激活内皮中的s -亚硝基化途径，诱导白细胞粘附和肿瘤细胞外渗，其机制涉及内皮细胞中VCAM-1细胞表面表达的增加。在此过程中，我们发现VCAM-1是s -亚硝基化靶标。NO信号和s -亚硝基化的抑制阻断了肿瘤细胞通过内皮单层的迁移。在体内模型中，s -亚硝基化抑制剂n -乙酰半胱氨酸（NAC）的存在抑制了肺转移瘤的数量，这与转移瘤中s -亚硝基化的VCAM-1水平降低有关。内皮中的s -亚硝基化激活增强VCAM-1表面定位的途径，促进白细胞结合和肿瘤细胞外渗导致转移。NAC被定位为一种重要的工具，可能被测试作为乳腺癌转移的联合治疗。
Nitric oxide is produced by different nitric oxide synthases isoforms. NO activates two signaling pathways, one dependent on soluble guanylate cyclase and protein kinase G, and other where NO post-translationally modifies proteins through S-nitrosylation, which is the modification induced by NO in free-thiol cysteines in proteins to form S-nitrosothiols. High levels of NO have been detected in blood of breast cancer patients and increased NOS activity has been detected in invasive breast tumors compared to benign or normal breast tissue, suggesting a positive correlation between NO biosynthesis, degree of malignancy and metastasis. During metastasis, the endothelium plays a key role allowing the adhesion of tumor cells, which is the first step in the extravasation process leading to metastasis. This step shares similarities with leukocyte adhesion to the endothelium, and it is plausible that it may also share some regulatory elements. The vascular cell adhesion molecule-1 (VCAM-1) expressed on the endothelial cell surface promotes interactions between the endothelium and tumor cells, as well as leukocytes. Data show that breast tumor cells adhere to areas in the vasculature where NO production is increased, however, the mechanisms involved are unknown. We report that the stimulation of endothelial cells with interleukin-8, and conditioned medium from breast tumor cells activates the S-nitrosylation pathway in the endothelium to induce leukocyte adhesion and tumor cell extravasation by a mechanism that involves an increased VCAM-1 cell surface expression in endothelial cells. We identified VCAM-1 as an S-nitrosylation target during this process. The inhibition of NO signaling and S-nitrosylation blocked the transmigration of tumor cells through endothelial monolayers. Using an in vivo model, the number of lung metastases was inhibited in the presence of the S-nitrosylation inhibitor N-acetylcysteine (NAC), which was correlated with lower levels of S-nitrosylated VCAM-1 in the metastases. S-Nitrosylation in the endothelium activates pathways that enhance VCAM-1 surface localization to promote binding of leukocytes and extravasation of tumor cells leading to metastasis. NAC is positioned as an important tool that might be tested as a co-therapy against breast cancer metastasis.
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影响因子：
6.4
作者：
ALBINI, A;DAGOSTINI, F;DEFLORA, S
通讯作者：
DEFLORA, S
影响因子：
17.1
作者：
Chung, Andrew W.;Anand, Kartik;Chang, Jenny C.
通讯作者：
Chang, Jenny C.
影响因子：
3.9
作者：
Ehrenfeld, Pamela;Cordova, Francisco;Sanchez, Fabiola A.
通讯作者：
Sanchez, Fabiola A.
影响因子：
4
作者：
Gao F;Lucke-Wold BP;Li X;Logsdon AF;Xu LC;Xu S;LaPenna KB;Wang H;Talukder MAH;Siedlecki CA;Huber JD;Rosen CL;He P
通讯作者：
He P
DOI：
10.1073/pnas.1401799111
发表时间：
2014-04-29
影响因子：
11.1
作者：
Heinecke, Julie L.;Ridnour, Lisa A.;Wink, David A.
通讯作者：
Wink, David A.