title: Thrombin-dependent modulation of β1-integrin-mediated signaling up-regulates prolidase and HIF-1α through p-FAK in colorectal cancer cells.
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 β(1)-integrin signaling. We studied the effects of echistatin (a well-known disintegrin) and thrombin (a serine protease capable of activation of integrin α(2)β(1) receptor) on prolidase activity and expressions of prolidase, α(2)β(1)-integrin receptor, focal adhesion kinase (FAK), MAP-kinases (ERK(1) and ERK(2)), 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 (pY(397)) under the effect of FAK inhibitor (1,2,4,5-benzenetetramine tetrahydrochloride). Although integrin α(2)β(1) 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.
authors: Department of Medicinal Chemistry, Medical University in Bialystok, Bialystok, Poland.
authors: Ewa
authors: E
authors: Karna
authors: Lukasz
authors: L
authors: Szoka
authors: Jerzy
authors: J
authors: Palka
mesh_terms: D000230:Adenocarcinoma; D000814:Aniline Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms; D004150:Dipeptidases / Q000235:genetics / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D039421:Integrin alpha2 / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects*; D013917:Thrombin / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: C539551:1,2,4,5-benzenetetraamine; D000814:Aniline Compounds; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D039421:Integrin alpha2; D019012:Integrin beta1; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C057986:echistatin; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D004150:Dipeptidases; C022449:proline dipeptidase; D013917:Thrombin