Tyrosine nitration of c-SRC tyrosine kinase in human pancreatic ductal adenocarcinoma
Tyrosine nitration of c-SRC tyrosine kinase in human pancreatic ductal adenocarcinoma
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DOI：
10.1006/abbi.2000.1799
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发表时间：
2000-05-15
影响因子：
3.9
通讯作者：
Thompson, JA
中科院分区：
文献类型：
--
作者：
MacMillan-Crow, LA;Greendorfer, JS;Thompson, JA
在胰腺肿瘤发生过程中，细胞存活和死亡之间的平衡被改变，导致肿瘤的侵袭性和对放疗和化疗的耐药性。局部氧化应激是调节程序性细胞死亡和生长的一种机制，可能有助于肿瘤的进展和抑制。我们最近的原位免疫组织化学研究表明，总硝基酪氨酸水平在人类胰腺导管腺癌中升高，硝基酪氨酸是活性氮物种过氧亚硝酸盐的足迹。在这项研究中，定量HPEC-EC技术表明，与正常胰腺提取物相比，人类胰腺肿瘤提取物的硝基酪氨酸总水平增加了21至97倍。对人胰腺肿瘤提取物的Western blot分析表明，酪氨酸的硝化作用仅限于少数特定的蛋白。免疫沉淀结合Western分析发现c-Src酪氨酸激酶是酪氨酸硝化和酪氨酸磷酸化的靶标。体外过氧亚硝酸盐处理人胰腺癌细胞导致c-Src激酶酪氨酸硝化和酪氨酸磷酸化增加，c-Src激酶活性增加（bbbb2倍），c-Src激酶与其下游底物接触的关联增加。总之，这些观察结果表明，过氧亚硝酸盐介导的酪氨酸硝化和c-Src激酶的酪氨酸磷酸化可能导致在胰腺导管腺癌生长和转移过程中观察到的酪氨酸激酶信号传导增强。(C) 2000年学术出版社。
During pancreatic tumorigenesis, the equilibrium between cell survival and cell death is altered, allowing aggressive neoplasia and resistance to radiation and chemotherapy. Local oxidative stress is one mechanism regulating programmed cell death and growth and may contribute to both tumor progression and suppression. Our recent in situ immunohistochemical studies demonstrated that levels of total nitrotyrosine, a footprint of the reactive nitrogen species peroxynitrite, are elevated in human pancreatic ductal adenocarcinomas. In this study, quantitative HPEC-EC techniques demonstrated a 21- to 97-fold increase in the overall levels of nitrotyrosine of human pancreatic tumor extracts compared to normal pancreatic extracts. Western blot analysis of human pancreatic tumor extracts showed that tyrosine nitration was restricted to a few specific proteins. Immunoprecipitation coupled with Western analysis identified c-Src tyrosine kinase as a target of both tyrosine nitration and tyrosine phosphorylation. Peroxynitrite treatment of human pancreatic carcinoma cells in vitro resulted in increased tyrosine nitration and tyrosine phosphorylation of c-Src kinase, increased (>2-fold) c-Src kinase activity, and increased association be tween c-Src kinase and its downstream substrate cortactin. Collectively, these observations suggest that peroxynitrite-mediated tyrosine nitration and tyrosine phosphorylation of c-Src kinase may lead to enhanced tyrosine kinase signaling observed during pancreatic ductal adenocarcinoma growth and metastasis. (C) 2000 Academic Press.