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首页> 外文期刊>Cell Research >uPAR expression under hypoxic conditions depends on iNOS modulated ERK phosphorylation in the MDA-MB-231 breast carcinoma cell line.
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uPAR expression under hypoxic conditions depends on iNOS modulated ERK phosphorylation in the MDA-MB-231 breast carcinoma cell line.

机译：低氧条件下的uPAR表达取决于MDA-MB-231乳腺癌细胞系中iNOS调控的ERK磷酸化。

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摘要

Urokinase plasminogen activator receptor (uPAR) plays a major role in cancer invasion and metastasis and uPAR expression is correlated with a poor prognosis in various cancer types. Moreover, the expression of uPAR is increased under hypoxic conditions. Nitric oxide (NO) and its metabolites produced by inducible nitric oxide synthase (iNOS) are important products of hypoxic stress, and NO may activate or modulate extracellular signal regulated kinase (ERK). Here, we evaluated uPA, uPAR, and activated ERK levels under hypoxic conditions, and the modulatory effects of iNOS and NO in the MDA-MB-231 human breast cancer cell line. Cells were incubated in a hypoxic or normoxic incubator and treated with PD98059 (a MEK 1/2 inhibitor, which abrogates ERK phosphorylation) and aminoguanidine (a selective iNOS inhibitor). uPAR expression, ERK phosphorylation, and uPA activity were found to be increased under hypoxic conditions. Moreover, when cells were treated with PD98059 under hypoxic conditions, uPAR was downregulated, whereas aminoguanidine markedly increased ERK phosphorylation in a dose dependent manner. Furthermore, aminoguanidine increased uPAR expression and prevented the inhibition of uPAR expression by PD98059. These results demonstrated that uPAR is induced by hypoxia and that increased uPAR expression is mediated by ERK phosphorylation, which in turn is modulated by iNOS/NO in MDA-MB-231 cells. We conclude that iNOS/NO downregulates the expression of uPAR under hypoxic conditions via ERK pathway modulation.Cell Research (2006) 16: 75-81. doi:10.1038/sj.cr.7310010; published online 16 January 2006.
机译：尿激酶纤溶酶原激活物受体（uPAR）在癌症的侵袭和转移中起主要作用，并且uPAR的表达与各种癌症的不良预后相关。而且，在缺氧条件下uPAR的表达增加。诱导型一氧化氮合酶（iNOS）产生的一氧化氮（NO）及其代谢产物是低氧应激的重要产物，NO可能激活或调节细胞外信号调节激酶（ERK）。在这里，我们评估了低氧条件下的uPA，uPA​​R和激活的ERK水平，以及iNOS和NO在MDA-MB-231人乳腺癌细胞系中的调节作用。将细胞在缺氧或常氧的培养箱中培养，并用PD98059（MEK 1/2抑制剂，可消除ERK磷酸化）和氨基胍（选择性iNOS抑制剂）处理。发现在低氧条件下，uPAR表达，ERK磷酸化和uPA活性增加。此外，当在缺氧条件下用PD98059处理细胞时，uPAR被下调，而氨基胍以剂量依赖性方式显着增加ERK磷酸化。此外，氨基胍增加了uPAR表达并阻止了PD98059对uPAR表达的抑制。这些结果表明，uPAR由缺氧诱导，uPAR表达的增加是由ERK磷酸化介导的，而ERK磷酸化又由iNOS / NO在MDA-MB-231细胞中调节。我们得出的结论是，在缺氧条件下，iNOS / NO通过ERK途径下调uPAR的表达。CellResearch（2006）16：75-81。 doi：10.1038 / sj.cr.7310010;在线发布于2006年1月16日。

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