دورية أكاديمية
The antiangiogenic effect of digitoxin is dependent on a ROS-elicited RhoA/ROCK pathway activation.
| العنوان: | The antiangiogenic effect of digitoxin is dependent on a ROS-elicited RhoA/ROCK pathway activation. |
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| المؤلفون: | Boscaro C; Department of Medicine, University of Padova, Padova, Italy., Schimdt G; Institute for Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Cignarella A; Department of Medicine, University of Padova, Padova, Italy., Dal Maso L; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy., Bolego C; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy., Trevisi L; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy. Electronic address: lucia.trevisi@unipd.it. |
| المصدر: | Biochemical pharmacology [Biochem Pharmacol] 2024 Apr; Vol. 222, pp. 116049. Date of Electronic Publication: 2024 Feb 09. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Science Country of Publication: England NLM ID: 0101032 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2968 (Electronic) Linking ISSN: 00062952 NLM ISO Abbreviation: Biochem Pharmacol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Oxford : Elsevier Science Original Publication: Oxford, New York [etc.] Paragamon Press. |
| مواضيع طبية MeSH: | Digitoxin*/pharmacology , NADPH Oxidases*/metabolism, Humans ; Reactive Oxygen Species/metabolism ; Human Umbilical Vein Endothelial Cells ; Focal Adhesion Kinase 1/metabolism ; Phosphorylation ; Cell Movement ; rhoA GTP-Binding Protein/metabolism ; rho-Associated Kinases/metabolism |
| مستخلص: | We previously showed that digitoxin inhibits angiogenesis and cancer cell proliferation and migration and these effects were associated to protein tyrosine kinase 2 (FAK) inhibition. Considering the interactions between FAK and Rho GTPases regulating cell cytoskeleton and movement, we investigated the involvement of RhoA and Rac1 in the antiangiogenic effect of digitoxin. Phalloidin staining of human umbilical vein endothelial cells (HUVECs) showed the formation of stress fibers in cells treated with 10 nM digitoxin. By Rhotekin- and Pak1- pull down assays, detecting the GTP-bound form of GTPases, we observed that digitoxin (10-25 nM) induced sustained (0.5-6 h) RhoA activation with no effect on Rac1. Furthermore, inhibition of HUVEC migration and capillary-like tube formation by digitoxin was counteracted by hindering RhoA-ROCK axis with RhoA silencing or Y-27632 treatment. Digitoxin did not decrease p190RhoGAP phosphorylation at Tyr1105 (a site targeted by FAK), suggesting that RhoA activation was independent from FAK inhibition. Because increasing evidence points to a redox regulation of RhoA, we measured intracellular ROS and found that digitoxin treatment enhanced ROS levels in a concentration-dependent manner (1-25 nM). Notably, the flavoprotein inhibitor DPI or the pan-NADPH oxidase (NOX) inhibitor VAS-2870 antagonized both ROS increase and RhoA activation by digitoxin. Our results provide evidence that inhibition of HUVEC migration and tube formation by digitoxin is dependent on ROS production by endothelial NOX, which leads to the activation of RhoA/ROCK pathway. Digitoxin effects on proteins regulating cytoskeletal organization and cell motility could have a wider impact on cancer progression, beyond the antiangiogenic activity. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Antiangiogenic drugs; Cardiac glycosides; Endothelial cell migration; NADPH oxidase; ROCK; ROS; RhoA GTPase |
| المشرفين على المادة: | 0 (Reactive Oxygen Species) E90NZP2L9U (Digitoxin) EC 2.7.10.2 (Focal Adhesion Kinase 1) EC 1.6.3.- (NADPH Oxidases) EC 3.6.5.2 (rhoA GTP-Binding Protein) EC 2.7.11.1 (rho-Associated Kinases) |
| تواريخ الأحداث: | Date Created: 20240211 Date Completed: 20240326 Latest Revision: 20240326 |
| رمز التحديث: | 20240326 |
| DOI: | 10.1016/j.bcp.2024.116049 |
| PMID: | 38342347 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1873-2968 |
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| DOI: | 10.1016/j.bcp.2024.116049 |