Methylglyoxal, a glycolysis metabolite, triggers metastasis through MEK/ERK/SMAD1 pathway activation in breast cancer
Abstract Background Elevated aerobic glycolysis rate is a biochemical alteration associated with malignant transformation and cancer progression. This metabolic shift unavoidably generates methylglyoxal (MG), a potent inducer of dicarbonyl stress through the formation of advanced glycation end produ...
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BMC
2019-01-01
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Series: | Breast Cancer Research |
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Online Access: | http://link.springer.com/article/10.1186/s13058-018-1095-7 |
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doaj-65d51f1a7dd24b1081a694086ad67b98 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Marie-Julie Nokin Justine Bellier Florence Durieux Olivier Peulen Gilles Rademaker Maude Gabriel Christine Monseur Benoit Charloteaux Lieven Verbeke Steven van Laere Patrick Roncarati Michael Herfs Charles Lambert Jean Scheijen Casper Schalkwijk Alain Colige Jo Caers Philippe Delvenne Andrei Turtoi Vincent Castronovo Akeila Bellahcène |
spellingShingle |
Marie-Julie Nokin Justine Bellier Florence Durieux Olivier Peulen Gilles Rademaker Maude Gabriel Christine Monseur Benoit Charloteaux Lieven Verbeke Steven van Laere Patrick Roncarati Michael Herfs Charles Lambert Jean Scheijen Casper Schalkwijk Alain Colige Jo Caers Philippe Delvenne Andrei Turtoi Vincent Castronovo Akeila Bellahcène Methylglyoxal, a glycolysis metabolite, triggers metastasis through MEK/ERK/SMAD1 pathway activation in breast cancer Breast Cancer Research Breast cancer Methylglyoxal SMAD1 Metastasis Carnosine MAPK |
author_facet |
Marie-Julie Nokin Justine Bellier Florence Durieux Olivier Peulen Gilles Rademaker Maude Gabriel Christine Monseur Benoit Charloteaux Lieven Verbeke Steven van Laere Patrick Roncarati Michael Herfs Charles Lambert Jean Scheijen Casper Schalkwijk Alain Colige Jo Caers Philippe Delvenne Andrei Turtoi Vincent Castronovo Akeila Bellahcène |
author_sort |
Marie-Julie Nokin |
title |
Methylglyoxal, a glycolysis metabolite, triggers metastasis through MEK/ERK/SMAD1 pathway activation in breast cancer |
title_short |
Methylglyoxal, a glycolysis metabolite, triggers metastasis through MEK/ERK/SMAD1 pathway activation in breast cancer |
title_full |
Methylglyoxal, a glycolysis metabolite, triggers metastasis through MEK/ERK/SMAD1 pathway activation in breast cancer |
title_fullStr |
Methylglyoxal, a glycolysis metabolite, triggers metastasis through MEK/ERK/SMAD1 pathway activation in breast cancer |
title_full_unstemmed |
Methylglyoxal, a glycolysis metabolite, triggers metastasis through MEK/ERK/SMAD1 pathway activation in breast cancer |
title_sort |
methylglyoxal, a glycolysis metabolite, triggers metastasis through mek/erk/smad1 pathway activation in breast cancer |
publisher |
BMC |
series |
Breast Cancer Research |
issn |
1465-542X |
publishDate |
2019-01-01 |
description |
Abstract Background Elevated aerobic glycolysis rate is a biochemical alteration associated with malignant transformation and cancer progression. This metabolic shift unavoidably generates methylglyoxal (MG), a potent inducer of dicarbonyl stress through the formation of advanced glycation end products (AGEs). We have previously shown that the silencing of glyoxalase 1 (GLO1), the main MG detoxifying enzyme, generates endogenous dicarbonyl stress resulting in enhanced growth and metastasis in vivo. However, the molecular mechanisms through which MG stress promotes metastasis development remain to be unveiled. Methods In this study, we used RNA sequencing analysis to investigate gene-expression profiling of GLO1-depleted breast cancer cells and we validated the regulated expression of selected genes of interest by RT-qPCR. Using in vitro and in vivo assays, we demonstrated the acquisition of a pro-metastatic phenotype related to dicarbonyl stress in MDA-MB-231, MDA-MB-468 and MCF7 breast cancer cellular models. Hyperactivation of MEK/ERK/SMAD1 pathway was evidenced using western blotting upon endogenous MG stress and exogenous MG treatment conditions. MEK and SMAD1 regulation of MG pro-metastatic signature genes in breast cancer cells was demonstrated by RT-qPCR. Results High-throughput transcriptome profiling of GLO1-depleted breast cancer cells highlighted a pro-metastatic signature that establishes novel connections between MG dicarbonyl stress, extracellular matrix (ECM) remodeling by neoplastic cells and enhanced cell migration. Mechanistically, we showed that these metastasis-related processes are functionally linked to MEK/ERK/SMAD1 cascade activation in breast cancer cells. We showed that sustained MEK/ERK activation in GLO1-depleted cells notably occurred through the down-regulation of the expression of dual specificity phosphatases in MG-stressed breast cancer cells. The use of carnosine and aminoguanidine, two potent MG scavengers, reversed MG stress effects in in vitro and in vivo experimental settings. Conclusions These results uncover for the first time the key role of MG dicarbonyl stress in the induction of ECM remodeling and the activation of migratory signaling pathways, both in favor of enhanced metastatic dissemination of breast cancer cells. Importantly, the efficient inhibition of mitogen-activated protein kinase (MAPK) signaling using MG scavengers further emphasizes the need to investigate their therapeutic potential across different malignancies. |
topic |
Breast cancer Methylglyoxal SMAD1 Metastasis Carnosine MAPK |
url |
http://link.springer.com/article/10.1186/s13058-018-1095-7 |
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doaj-65d51f1a7dd24b1081a694086ad67b982021-04-02T14:33:43ZengBMCBreast Cancer Research1465-542X2019-01-0121111910.1186/s13058-018-1095-7Methylglyoxal, a glycolysis metabolite, triggers metastasis through MEK/ERK/SMAD1 pathway activation in breast cancerMarie-Julie Nokin0Justine Bellier1Florence Durieux2Olivier Peulen3Gilles Rademaker4Maude Gabriel5Christine Monseur6Benoit Charloteaux7Lieven Verbeke8Steven van Laere9Patrick Roncarati10Michael Herfs11Charles Lambert12Jean Scheijen13Casper Schalkwijk14Alain Colige15Jo Caers16Philippe Delvenne17Andrei Turtoi18Vincent Castronovo19Akeila Bellahcène20Metastasis Research Laboratory, GIGA-Cancer, University of Liège (ULiège)Metastasis Research Laboratory, GIGA-Cancer, University of Liège (ULiège)Metastasis Research Laboratory, GIGA-Cancer, University of Liège (ULiège)Metastasis Research Laboratory, GIGA-Cancer, University of Liège (ULiège)Metastasis Research Laboratory, GIGA-Cancer, University of Liège (ULiège)Metastasis Research Laboratory, GIGA-Cancer, University of Liège (ULiège)Metastasis Research Laboratory, GIGA-Cancer, University of Liège (ULiège)Genomics Platform, GIGA, ULiègeDepartment of Information Technology, Ghent UniversityTranslational Cancer Research Unit, University of AntwerpLaboratory of Experimental Pathology, GIGA-Cancer, ULiègeLaboratory of Experimental Pathology, GIGA-Cancer, ULiègeLaboratory of Connective Tissues Biology, GIGA-Cancer, ULiègeLaboratory for Metabolism and Vascular Medicine, Department of Internal Medicine, Maastricht UniversityLaboratory for Metabolism and Vascular Medicine, Department of Internal Medicine, Maastricht UniversityLaboratory of Connective Tissues Biology, GIGA-Cancer, ULiègeLaboratory of Hematology, GIGA-Inflammation, Infection and Immunity, ULiègeLaboratory of Experimental Pathology, GIGA-Cancer, ULiègeInstitut de Recherche en Cancérologie de Montpellier, Inserm U1194Metastasis Research Laboratory, GIGA-Cancer, University of Liège (ULiège)Metastasis Research Laboratory, GIGA-Cancer, University of Liège (ULiège)Abstract Background Elevated aerobic glycolysis rate is a biochemical alteration associated with malignant transformation and cancer progression. This metabolic shift unavoidably generates methylglyoxal (MG), a potent inducer of dicarbonyl stress through the formation of advanced glycation end products (AGEs). We have previously shown that the silencing of glyoxalase 1 (GLO1), the main MG detoxifying enzyme, generates endogenous dicarbonyl stress resulting in enhanced growth and metastasis in vivo. However, the molecular mechanisms through which MG stress promotes metastasis development remain to be unveiled. Methods In this study, we used RNA sequencing analysis to investigate gene-expression profiling of GLO1-depleted breast cancer cells and we validated the regulated expression of selected genes of interest by RT-qPCR. Using in vitro and in vivo assays, we demonstrated the acquisition of a pro-metastatic phenotype related to dicarbonyl stress in MDA-MB-231, MDA-MB-468 and MCF7 breast cancer cellular models. Hyperactivation of MEK/ERK/SMAD1 pathway was evidenced using western blotting upon endogenous MG stress and exogenous MG treatment conditions. MEK and SMAD1 regulation of MG pro-metastatic signature genes in breast cancer cells was demonstrated by RT-qPCR. Results High-throughput transcriptome profiling of GLO1-depleted breast cancer cells highlighted a pro-metastatic signature that establishes novel connections between MG dicarbonyl stress, extracellular matrix (ECM) remodeling by neoplastic cells and enhanced cell migration. Mechanistically, we showed that these metastasis-related processes are functionally linked to MEK/ERK/SMAD1 cascade activation in breast cancer cells. We showed that sustained MEK/ERK activation in GLO1-depleted cells notably occurred through the down-regulation of the expression of dual specificity phosphatases in MG-stressed breast cancer cells. The use of carnosine and aminoguanidine, two potent MG scavengers, reversed MG stress effects in in vitro and in vivo experimental settings. Conclusions These results uncover for the first time the key role of MG dicarbonyl stress in the induction of ECM remodeling and the activation of migratory signaling pathways, both in favor of enhanced metastatic dissemination of breast cancer cells. Importantly, the efficient inhibition of mitogen-activated protein kinase (MAPK) signaling using MG scavengers further emphasizes the need to investigate their therapeutic potential across different malignancies.http://link.springer.com/article/10.1186/s13058-018-1095-7Breast cancerMethylglyoxalSMAD1MetastasisCarnosineMAPK |