NOX1 and PRDX6 synergistically support migration and invasiveness of hepatocellular carcinoma cells through enhanced NADPH oxidase activity
The NADPH oxidase 1 (NOX1) complex formed by proteins NOX1, p22phox, NOXO1, NOXA1, and RAC1 plays an important role in the generation of superoxide and other reactive oxygen species (ROS) which are involved in normal and pathological cell functions due to their effects on diverse cell signaling path...
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Elsevier
2023-12-01
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Series: | Advances in Redox Research |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2667137923000206 |
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author | Daniel J. Lagal J. Antonio Bárcena Raquel Requejo-Aguilar C. Alicia Padilla Thomas L. Leto |
author_facet | Daniel J. Lagal J. Antonio Bárcena Raquel Requejo-Aguilar C. Alicia Padilla Thomas L. Leto |
author_sort | Daniel J. Lagal |
collection | DOAJ |
description | The NADPH oxidase 1 (NOX1) complex formed by proteins NOX1, p22phox, NOXO1, NOXA1, and RAC1 plays an important role in the generation of superoxide and other reactive oxygen species (ROS) which are involved in normal and pathological cell functions due to their effects on diverse cell signaling pathways. Cell migration and invasiveness are at the origin of tumor metastasis during cancer progression which involves a process of cellular de-differentiation known as the epithelial-mesenchymal transition (EMT). During EMT cells lose their polarized epithelial phenotype and express mesenchymal marker proteins that enable cytoskeletal rearrangements promoting cell migration, expression and activation of matrix metalloproteinases (MMPs), tissue remodeling, and cell invasion during metastasis. In this work, we explored the importance of the peroxiredoxin 6 (PRDX6)-NOX1 enzyme interaction leading to NOXA1 protein stabilization and increased levels of superoxide produced by NOX in hepatocarcinoma cells. This increase was accompanied by higher levels of N-cadherin and MMP2, correlating with a greater capacity for cell migration and invasiveness of SNU475 hepatocarcinoma cells. The increase in superoxide and the associated downstream effects on cancer progression were suppressed when phospholipase A2 or peroxidase activities of PRDX6 were abolished by site-directed mutagenesis, reinforcing the importance of these catalytic activities in supporting NOX1-based superoxide generation. Overall, these results demonstrate a clear functional cooperation between NOX1 and PRDX6 catalytic activities which generate higher levels of ROS production, resulting in a more aggressive tumor phenotype. |
first_indexed | 2024-03-09T01:25:15Z |
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institution | Directory Open Access Journal |
issn | 2667-1379 |
language | English |
last_indexed | 2024-03-09T01:25:15Z |
publishDate | 2023-12-01 |
publisher | Elsevier |
record_format | Article |
series | Advances in Redox Research |
spelling | doaj.art-4b13956b20454fb898a7e2972aa6a0fc2023-12-10T06:18:52ZengElsevierAdvances in Redox Research2667-13792023-12-019100080NOX1 and PRDX6 synergistically support migration and invasiveness of hepatocellular carcinoma cells through enhanced NADPH oxidase activityDaniel J. Lagal0J. Antonio Bárcena1Raquel Requejo-Aguilar2C. Alicia Padilla3Thomas L. Leto4Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Building 29B, Room 5NN06, Bethesda, MD 20892, USA; Biochemistry and Molecular Biology Department, University of Córdoba, Córdoba, SpainBiochemistry and Molecular Biology Department, University of Córdoba, Córdoba, Spain; Maimónides Biomedical Research Institute of Córdoba (IMIBIC), SpainBiochemistry and Molecular Biology Department, University of Córdoba, Córdoba, Spain; Maimónides Biomedical Research Institute of Córdoba (IMIBIC), SpainBiochemistry and Molecular Biology Department, University of Córdoba, Córdoba, Spain; Maimónides Biomedical Research Institute of Córdoba (IMIBIC), SpainLaboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Building 29B, Room 5NN06, Bethesda, MD 20892, USA; Corresponding author.The NADPH oxidase 1 (NOX1) complex formed by proteins NOX1, p22phox, NOXO1, NOXA1, and RAC1 plays an important role in the generation of superoxide and other reactive oxygen species (ROS) which are involved in normal and pathological cell functions due to their effects on diverse cell signaling pathways. Cell migration and invasiveness are at the origin of tumor metastasis during cancer progression which involves a process of cellular de-differentiation known as the epithelial-mesenchymal transition (EMT). During EMT cells lose their polarized epithelial phenotype and express mesenchymal marker proteins that enable cytoskeletal rearrangements promoting cell migration, expression and activation of matrix metalloproteinases (MMPs), tissue remodeling, and cell invasion during metastasis. In this work, we explored the importance of the peroxiredoxin 6 (PRDX6)-NOX1 enzyme interaction leading to NOXA1 protein stabilization and increased levels of superoxide produced by NOX in hepatocarcinoma cells. This increase was accompanied by higher levels of N-cadherin and MMP2, correlating with a greater capacity for cell migration and invasiveness of SNU475 hepatocarcinoma cells. The increase in superoxide and the associated downstream effects on cancer progression were suppressed when phospholipase A2 or peroxidase activities of PRDX6 were abolished by site-directed mutagenesis, reinforcing the importance of these catalytic activities in supporting NOX1-based superoxide generation. Overall, these results demonstrate a clear functional cooperation between NOX1 and PRDX6 catalytic activities which generate higher levels of ROS production, resulting in a more aggressive tumor phenotype.http://www.sciencedirect.com/science/article/pii/S2667137923000206NOX1NADPH oxidase 1PRDX6SuperoxideMesenchymal phenotypeCancer progression |
spellingShingle | Daniel J. Lagal J. Antonio Bárcena Raquel Requejo-Aguilar C. Alicia Padilla Thomas L. Leto NOX1 and PRDX6 synergistically support migration and invasiveness of hepatocellular carcinoma cells through enhanced NADPH oxidase activity Advances in Redox Research NOX1 NADPH oxidase 1 PRDX6 Superoxide Mesenchymal phenotype Cancer progression |
title | NOX1 and PRDX6 synergistically support migration and invasiveness of hepatocellular carcinoma cells through enhanced NADPH oxidase activity |
title_full | NOX1 and PRDX6 synergistically support migration and invasiveness of hepatocellular carcinoma cells through enhanced NADPH oxidase activity |
title_fullStr | NOX1 and PRDX6 synergistically support migration and invasiveness of hepatocellular carcinoma cells through enhanced NADPH oxidase activity |
title_full_unstemmed | NOX1 and PRDX6 synergistically support migration and invasiveness of hepatocellular carcinoma cells through enhanced NADPH oxidase activity |
title_short | NOX1 and PRDX6 synergistically support migration and invasiveness of hepatocellular carcinoma cells through enhanced NADPH oxidase activity |
title_sort | nox1 and prdx6 synergistically support migration and invasiveness of hepatocellular carcinoma cells through enhanced nadph oxidase activity |
topic | NOX1 NADPH oxidase 1 PRDX6 Superoxide Mesenchymal phenotype Cancer progression |
url | http://www.sciencedirect.com/science/article/pii/S2667137923000206 |
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