Abstract
Methylglyoxal (MG) is a potent inducer of advanced glycation end products (AGEs). MG, long considered a highly cytotoxic molecule with potential anticancer value, is now being re-evaluated to a protumorigenic agent in some malignancies. Anaplastic thyroid cancer (ATC) is an extremely aggressive and highly lethal cancer for which conventional therapies have proved ineffective. Successful therapeutic intervention in ATC is undermined by our poor understanding of its molecular etiology. In the attempt to understand the role of MG in ATC aggressiveness, we used immunohistochemistry to examine the level of MG protein adducts in ATC and slow-growing papillary thyroid cancer (PTC). We detected a high level of MG adducts in ATC compared to PTC ones, suggesting a protumor role for MG-mediated dicarbonyl stress in ATC. Accordingly, MG adduct accumulation in ATC cells in vitro was associated with a marked mesenchymal phenotype and increased migration/invasion, which were both reversed by aminoguanidine (AG)—a scavenger of MG—and resveratrol—an activator of Glyoxalase 1 (Glo1), the key metabolizing enzyme of MG. Our study represents the first demonstration that MG, via AGEs, acts as a tumor-promoting factor in ATC and suggests that MG scavengers and/or Glo1 activators merit investigations as potential therapeutic strategies for this malignancy.
Highlights
Methylglyoxal (MG) is a dicarbonyl compound with a low molecular mass mainly generated in cells through the spontaneous degradation of triose phosphate intermediates of glycolysis [1].MG is a powerful glycating agent and is much more reactive than parent glucose in glycation processes
MG-H1 Adducts Accumulated in Anaplastic Thyroid Cancer (ATC) Tissues When Compared with
These results suggested that the accumulation of MG-mediated dicarbonyl stress observed in Anaplastic thyroid cancer (ATC) tumors was consequent to a decreased functionality of Glyoxalase 1 (Glo1)
Summary
Methylglyoxal (MG) is a dicarbonyl compound with a low molecular mass mainly generated in cells through the spontaneous degradation of triose phosphate intermediates of glycolysis [1]. There is evidence that some MG-derived AGEs, including AP, are endowed with antioxidant properties [14] These apparently divergent functions imply that MG, like other reactive species, may exert different or even opposite biological effects, depending on its levels [15] and the cellular context. We showed that high tumor MG adduct accumulation was associated with low Glo activity levels and aggressiveness of ATC patients. Our study represents the first demonstration of a correlation between dicarbonyl stress and ATC aggressiveness and suggests that blockade of dicarbonyl stress by MG scavengers and/or Glo activators merit investigations as a potential new therapeutic strategy for the treatment of this lethal disease
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