Abstract
BackgroundElevated 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.MethodsIn 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.ResultsHigh-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.ConclusionsThese 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.
Highlights
Elevated aerobic glycolysis rate is a biochemical alteration associated with malignant transformation and cancer progression
We have further demonstrated that mitogen-activated protein kinase kinase (MEK)/extracellular signal-related protein kinase (ERK)-sustained activation in glyoxalase 1 (GLO1)-depleted cells notably occurs through the down-regulation of dual specificity phosphate 5 (DUSP5) phosphatase expression upon MG stress in breast cancer cells
RNASeq analysis of GLO1-depleted MDA-MB-231 breast cancer cells highlights a pro-metastatic signature In an attempt to unveil the mechanisms by which MG stress enhances the metastatic potential of breast cancer cells, we performed genome-wide messenger RNA profiling of MDA-MB-231 GLO1-depleted cells
Summary
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). A key hallmark of cancer cells is their metabolic reprogramming consisting of enhanced aerobic glycolysis over oxidative respiration This so called “Warburg effect” leads to the accumulation of methylglyoxal (MG), a highly toxic and reactive dicarbonyl, that spontaneously glycates proteins, nucleic acids and lipids [1]. Using breast and glioblastoma cell lines, our group has demonstrated that low doses of MG promote tumor growth rather than inhibit it. This hormesis effect of MG seemingly reconciles contrasting data in the literature [9]. At sub-toxic doses, MG turns out to be beneficial to cancer cells as they acquire resistance to apoptosis and enhanced growth properties
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