A novel mechanism of methylglyoxal cytotoxicity in prostate cancer cells.

Methylglyoxal (MG) is one of the most powerful glycating agents of proteins and other important cellular components and has been shown to be toxic to cultured cells. MG cytotoxicity appear to occur through cell-cycle arrest but, more often, through induction of apoptosis. In this study we examined whether, and through which molecular mechanism, MG affect the growth of poorly aggressive LNCaP and invasive PC3 human prostate cancer cells, where its role has not been exhaustively investigated yet. We demonstrated that MG is cytotoxic on LNCaP and PC3 and that such cytotoxicity occurs not via cell proliferation but apoptosis control. Moreover, we demonstrated that MG cytotoxicity, potentiated by the silencing of its major scavenging enzyme Glyoxalase I, occurred via different apoptotic responses in LNCaP and PC3 cells, that also showed a different susceptibility to this metabolite. Finally, we showed that the observed MG apoptogenic role involved different molecular pathways, specifically mediated by MG or MG-derived argpyrimidine (AP) intracellular accumulation and NFkB signaling-pathway. In particular, in LNCaP cells, MG, through the accumulation of AP, desensitized the key cell survival NF-kB signaling pathway, which was consistent with the modulation of NF-kB-regulated genes, triggering a mitochondrial apoptotic pathway. The results suggest that this physiological compound merits investigation as a potential chemo-preventive/-therapeutic agent, in differently aggressive prostate cancers.