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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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Abstract

Products of prolidase [E.C. 3.4.13.9] activity, proline or hydroxyproline, contribute to up-regulation of hypoxia-inducible factor-1α (HIF-1α). Prolidase activity is regulated by β1-integrin signaling. We studied the effects of echistatin (a well-known disintegrin) and thrombin (a serine protease capable of activation of integrin α2β1 receptor) on prolidase activity and expressions of prolidase, α2β1-integrin receptor, focal adhesion kinase (FAK), MAP-kinases (ERK1 and ERK2), and nuclear HIF-1α 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 (pY397) under the effect of FAK inhibitor (1,2,4,5-benzenetetramine tetrahydrochloride). Although integrin α2β1 receptor expression was not affected by thrombin, the signaling induced by thrombin up-regulated nuclear HIF-1α 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.

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Authors and Affiliations

  1. Department of Medicinal Chemistry, Medical University in Bialystok, ul. Kilinskiego 1 Street, 15-089, Bialystok, Poland

    Ewa Karna, Lukasz Szoka & Jerzy Palka

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  1. Ewa Karna
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  2. Lukasz Szoka
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  3. Jerzy Palka
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Correspondence to Jerzy Palka.

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Karna, E., Szoka, L. & Palka, J. Thrombin-dependent modulation of β1-integrin-mediated signaling up-regulates prolidase and HIF-1α through p-FAK in colorectal cancer cells. Mol Cell Biochem 361, 235–241 (2012). https://doi.org/10.1007/s11010-011-1108-7

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