Thrombin-dependent modulation of β1-integrin-mediated signaling up-regulates prolidase and HIF-1α through p-FAK in colorectal cancer cells
Thrombin-dependent modulation of β1-integrin-mediated signaling up-regulates prolidase and HIF-1α through p-FAK in colorectal cancer cells
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DOI：
10.1007/s11010-011-1108-7
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发表时间：
2012-02-01
影响因子：
4.3
通讯作者：
Palka, Jerzy
中科院分区：
文献类型：
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作者：
Karna, Ewa;Szoka, Lukasz;Palka, Jerzy
脯氨酸酶的产物[E.C. 3.4.13.9]活性，脯氨酸或羟脯氨酸，有助于缺氧诱导因子1α（HIF-1α）的上调。脯氨酸酶活性受β(1)-整合素信号传导调节。我们研究了 echistatin（一种众所周知的解整合素）和凝血酶（一种能够激活整合素 α(2)β(1) 受体的丝氨酸蛋白酶）对脯氨酸酶活性以及脯氨酸酶、α(2)β(1)-整合素受体、粘着斑激酶 (FAK)、MAP 激酶（ERK1 和 ERK2）和核 HIF-1 α 表达的影响。 人结肠腺癌细胞（DLD-1）。已发现用凝血酶处理细胞有助于减少脯氨酸酶的表达，同时增加其磷酸化，从而维持酶活性。在FAK抑制剂（1,2,4,5-苯四胺四盐酸盐）的作用下，该现象伴随着FAK自磷酸化抑制（pY(397)）的凝血酶依赖性恢复。尽管整合素α(2)β(1)受体表达不受凝血酶影响，但凝血酶诱导的信号传导上调核HIF-1α表达。伴随着 MAP 激酶、ERK1 和 ERK2 表达的增加。这表明通过 p-FAK 的整合素依赖性信号在 DLD-1 细胞中上调，并且它可能代表抗癌治疗的潜在靶点。
Products of prolidase [E.C. 3.4.13.9] activity, proline or hydroxyproline, contribute to up-regulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha). Prolidase activity is regulated by beta(1)-integrin signaling. We studied the effects of echistatin (a well-known disintegrin) and thrombin (a serine protease capable of activation of integrin alpha(2)beta(1) receptor) on prolidase activity and expressions of prolidase, alpha(2)beta(1)-integrin receptor, focal adhesion kinase (FAK), MAP-kinases (ERK1 and ERK2), and nuclear HIF-1 alpha in human colon adenocarcinoma (DLD-1) cells. It has been found that treatment of the cells with thrombin contributes to decrease in the expression of prolidase and simultaneously increase in its phosphorylation, resulting in maintenance of the enzyme activity. The phenomenon was accompanied by thrombin-dependent recovery of depressed autophosphorylation of FAK (pY(397)) under the effect of FAK inhibitor (1,2,4,5-benzenetetramine tetrahydrochloride). Although integrin alpha(2)beta(1) receptor expression was not affected by thrombin, the signaling induced by thrombin up-regulated nuclear HIF-1 alpha expression. It was accompanied by increase in the expression of MAP kinases, ERK1 and ERK2. It suggests that integrin-dependent signaling through p-FAK is up-regulated in DLD-1 cells and it may represent potential target for anti-cancer therapy.