PO-226 Dicarbonyl stress induces ECM remodelling and MAPK signalling activation in metastatic breast cancer cells

Abstract

IntroductionTumour cells use glycolysis rather than mitochondrial respiration to produce their energy. Methylglyoxal (MG), a highly reactive side-product of glycolysis, glycates proteins and nucleic acids thereby inducing dicarbonyl stress in cancer cells. In previous studies, we reported that the accumulation of MG-protein adducts is a constant feature in breast and colon tumours when compared with normal tissues. More recently, we demonstrated that the silencing of glyoxalase 1 (GLO1), the principal MG detoxifying enzyme, in human breast cancer cells generates endogenous dicarbonyl stress resulting in enhanced growth and metastasis in vivo.Material and methodsWe performed a high-throughput transcriptome profiling of stably GLO1-silenced MDA-MB-231 breast cancer clones in order to identify significant gene expression alterations underlying enhanced invasive and metastatic capacity of breast cancer cells upon MG stress.Results and discussionsRNA-Sequencing analysis of GLO1-depleted breast cancer cells pointed to a pro-metastatic signature notably linked to ECM remodelling with the overexpression of collagens and tenascin C. GLO1-depleted cancer cells showed increased anchorage independent growth and invasion abilities, that were reverted in presence of MG scavengers thus connecting these aggressive features with MG stress. Mechanistically, we demonstrated that MG stress induces the activation of MEK/ERK pathway which signals through activated SMAD1.ConclusionOur data show for the first time that neoplasic cells under MG stress directly contribute to ECM changes and MAPK pathway activation which sustain their pro-metastatic phenotype. Based on our data, we propose that the use of MG scavengers represent a promising therapeutic strategy to block the progression of highly glycolytic tumours.