Abstract
Metabolic reprogramming toward aerobic glycolysis unavoidably induces methylglyoxal (MG) formation in cancer cells. MG mediates the glycation of proteins to form advanced glycation end products (AGEs). We have recently demonstrated that MG-induced AGEs are a common feature of breast cancer. Little is known regarding the impact of MG-mediated carbonyl stress on tumor progression. Breast tumors with MG stress presented with high nuclear YAP, a key transcriptional co-activator regulating tumor growth and invasion. Elevated MG levels resulted in sustained YAP nuclear localization/activity that could be reverted using Carnosine, a scavenger for MG. MG treatment affected Hsp90 chaperone activity and decreased its binding to LATS1, a key kinase of the Hippo pathway. Cancer cells with high MG stress showed enhanced growth and metastatic potential in vivo. These findings reinforce the cumulative evidence pointing to hyperglycemia as a risk factor for cancer incidence and bring renewed interest in MG scavengers for cancer treatment.
Highlights
Unlike normal cells, cancer cells mainly rely on glycolysis to generate energy needed for cellular processes even in normoxia conditions
Methylglyoxal adducts and nuclear Yes-associated protein (YAP) are positively correlated in human breast cancer At the molecular level, a predictable consequence of the glycolytic switch in cancer cells is the induction of carbonyl stress (Figure 1A)
Data were analyzed using one-way ANOVA followed by Dunnett post-test and shown as the mean values ± Standard Error Mean (SEM) of three independent experiments. (C) Lactate level measured using 1H-Nuclear magnetic resonance (NMR) increased in highly glycolytic MDA-MB-231 cells cultured in high glucose (HG) compared to low glucose (LG) while MCF7 low glycolytic cells did not. (D and E) MG quantification using both FACS MBo mean fluorescence intensity (MFI) and LC-MS/MS analysis on conditioned medium in the indicated conditions as described under ’Materials and methods’ section
Summary
Cancer cells mainly rely on glycolysis to generate energy needed for cellular processes even in normoxia conditions. This process referred to aerobic glycolysis or the ’Warburg. Aerobic glycolysis is less efficient than respiration to generate ATP, we know that it effectively supports the anabolic requirements associated with cancer cell growth and proliferation. Alpha-oxoaldehydes are up to 20,000-fold more reactive than glucose in glycation processes (Turk, 2010), and it is expected that 1% to 5% of proteins in cells are modified by MG (Rabbani and Thornalley, 2014). MG interaction with amino groups of proteins notably leads to the formation of advanced glycation end products (AGEs) called hydroimidazolones (MG-H) and argpyrimidines (Thornalley, 1996). The disturbance in the balance between endogenous reactive carbonyl species generation and the ability to counteract their harmful effects is defined as the carbonyl stress
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