Cargando…

Exogenous C2 Ceramide Suppresses Matrix Metalloproteinase Gene Expression by Inhibiting ROS Production and MAPK Signaling Pathways in PMA-Stimulated Human Astroglioma Cells

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases, which play a pivotal role in invasion, migration, and angiogenesis of glioma. Therefore, controlling MMPs is potentially an important therapeutic strategy for glioma. In the present study, we found that exogenous cell-pe...

Descripción completa

Detalles Bibliográficos
Autores principales: Jung, Ji-Sun, Ahn, Young-Ho, Moon, Byung-In, Kim, Hee-Sun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848933/
https://www.ncbi.nlm.nih.gov/pubmed/27043542
http://dx.doi.org/10.3390/ijms17040477
_version_ 1782429451144921088
author Jung, Ji-Sun
Ahn, Young-Ho
Moon, Byung-In
Kim, Hee-Sun
author_facet Jung, Ji-Sun
Ahn, Young-Ho
Moon, Byung-In
Kim, Hee-Sun
author_sort Jung, Ji-Sun
collection PubMed
description Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases, which play a pivotal role in invasion, migration, and angiogenesis of glioma. Therefore, controlling MMPs is potentially an important therapeutic strategy for glioma. In the present study, we found that exogenous cell-permeable short-chain C2 ceramide inhibits phorbol myristate acetate (PMA)-induced MMP-1, -3, and -9 gene expressions in U87MG and U373MG human astroglioma cells. In addition, C2 ceramide inhibited the protein secretion and enzymatic activities of MMP-1, -3, and -9. The Matrigel invasion assay and wound healing assay showed that C2 ceramide suppresses the in vitro invasion and migration of glioma cells, which appears to be involved in strong inhibition of MMPs by C2 ceramide. Subsequent mechanistic studies revealed that C2 ceramide inhibits PMA-induced mitogen-activated protein kinase (MAPK) phosphorylation and nuclear factor (NF)-κB/activator protein (AP)-1 DNA binding activities. Furthermore, C2 ceramide significantly inhibited PMA-induced reactive oxygen species (ROS) production and NADPH oxidase 4 (NOX4) expression, and inhibition of ROS by diphenylene iodonium (DPI, NADPH oxidase inhibitor) mimicked the effects of C2 ceramide on MMP expression and NF-κB/AP-1 via inhibition of p38 MAPK. The results suggest C2 ceramide inhibits MMP expression and glioma invasion, at least partly, by modulating ROS-p38 MAPK signaling axis and other MAPK signaling pathways.
format Online
Article
Text
id pubmed-4848933
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-48489332016-05-04 Exogenous C2 Ceramide Suppresses Matrix Metalloproteinase Gene Expression by Inhibiting ROS Production and MAPK Signaling Pathways in PMA-Stimulated Human Astroglioma Cells Jung, Ji-Sun Ahn, Young-Ho Moon, Byung-In Kim, Hee-Sun Int J Mol Sci Article Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases, which play a pivotal role in invasion, migration, and angiogenesis of glioma. Therefore, controlling MMPs is potentially an important therapeutic strategy for glioma. In the present study, we found that exogenous cell-permeable short-chain C2 ceramide inhibits phorbol myristate acetate (PMA)-induced MMP-1, -3, and -9 gene expressions in U87MG and U373MG human astroglioma cells. In addition, C2 ceramide inhibited the protein secretion and enzymatic activities of MMP-1, -3, and -9. The Matrigel invasion assay and wound healing assay showed that C2 ceramide suppresses the in vitro invasion and migration of glioma cells, which appears to be involved in strong inhibition of MMPs by C2 ceramide. Subsequent mechanistic studies revealed that C2 ceramide inhibits PMA-induced mitogen-activated protein kinase (MAPK) phosphorylation and nuclear factor (NF)-κB/activator protein (AP)-1 DNA binding activities. Furthermore, C2 ceramide significantly inhibited PMA-induced reactive oxygen species (ROS) production and NADPH oxidase 4 (NOX4) expression, and inhibition of ROS by diphenylene iodonium (DPI, NADPH oxidase inhibitor) mimicked the effects of C2 ceramide on MMP expression and NF-κB/AP-1 via inhibition of p38 MAPK. The results suggest C2 ceramide inhibits MMP expression and glioma invasion, at least partly, by modulating ROS-p38 MAPK signaling axis and other MAPK signaling pathways. MDPI 2016-03-31 /pmc/articles/PMC4848933/ /pubmed/27043542 http://dx.doi.org/10.3390/ijms17040477 Text en © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Jung, Ji-Sun
Ahn, Young-Ho
Moon, Byung-In
Kim, Hee-Sun
Exogenous C2 Ceramide Suppresses Matrix Metalloproteinase Gene Expression by Inhibiting ROS Production and MAPK Signaling Pathways in PMA-Stimulated Human Astroglioma Cells
title Exogenous C2 Ceramide Suppresses Matrix Metalloproteinase Gene Expression by Inhibiting ROS Production and MAPK Signaling Pathways in PMA-Stimulated Human Astroglioma Cells
title_full Exogenous C2 Ceramide Suppresses Matrix Metalloproteinase Gene Expression by Inhibiting ROS Production and MAPK Signaling Pathways in PMA-Stimulated Human Astroglioma Cells
title_fullStr Exogenous C2 Ceramide Suppresses Matrix Metalloproteinase Gene Expression by Inhibiting ROS Production and MAPK Signaling Pathways in PMA-Stimulated Human Astroglioma Cells
title_full_unstemmed Exogenous C2 Ceramide Suppresses Matrix Metalloproteinase Gene Expression by Inhibiting ROS Production and MAPK Signaling Pathways in PMA-Stimulated Human Astroglioma Cells
title_short Exogenous C2 Ceramide Suppresses Matrix Metalloproteinase Gene Expression by Inhibiting ROS Production and MAPK Signaling Pathways in PMA-Stimulated Human Astroglioma Cells
title_sort exogenous c2 ceramide suppresses matrix metalloproteinase gene expression by inhibiting ros production and mapk signaling pathways in pma-stimulated human astroglioma cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848933/
https://www.ncbi.nlm.nih.gov/pubmed/27043542
http://dx.doi.org/10.3390/ijms17040477
work_keys_str_mv AT jungjisun exogenousc2ceramidesuppressesmatrixmetalloproteinasegeneexpressionbyinhibitingrosproductionandmapksignalingpathwaysinpmastimulatedhumanastrogliomacells
AT ahnyoungho exogenousc2ceramidesuppressesmatrixmetalloproteinasegeneexpressionbyinhibitingrosproductionandmapksignalingpathwaysinpmastimulatedhumanastrogliomacells
AT moonbyungin exogenousc2ceramidesuppressesmatrixmetalloproteinasegeneexpressionbyinhibitingrosproductionandmapksignalingpathwaysinpmastimulatedhumanastrogliomacells
AT kimheesun exogenousc2ceramidesuppressesmatrixmetalloproteinasegeneexpressionbyinhibitingrosproductionandmapksignalingpathwaysinpmastimulatedhumanastrogliomacells