Molecular Medicine in Practice Targeting the Glyoxalase Pathway Enhances TRAIL Efficacy in Cancer Cells by Downregulating the Expression of Antiapoptotic Molecules

Methylglyoxal is an essential component in glycolysis and is known tobe an inducer of apoptosis.Glyoxalase I (GLO1) metabolizes and inactivates methylglyoxal. GLO1 is known to be overexpressed in cancer cells and causes resistance to anticancer agents.We show for the first time that methylglyoxal treatment or the silencing ofGLO1enhances sensitivity to thepromising anticancer agentTRAIL inmalignant tumor cells.Methylglyoxal suppressed the expression of antiapoptotic factors, X-linked inhibitor of apoptosis protein (XIAP), survivin, cIAP1, Bcl-2, and Bcl-xL,without affecting TRAIL receptors, DR4 andDR5. Knockdown of XIAP or survivin by siRNA also enhanced TRAIL-induced apoptosis, indicating that downregulation of XIAP and survivin expression by methylglyoxal contributes to the enhancement of TRAIL activity. Furthermore, methylglyoxal decreased NF-kB activity with or without TRAIL treatment. On the other hand, the knockdown of GLO1 by siRNA enhanced TRAIL-induced apoptosis via the downregulation of XIAP and survivin expression. In conclusion, our results strongly suggest that sensitivity to TRAIL is increased by inhibition of the glyoxalase pathway and that the combination of TRAIL with methylglyoxal or glyoxalase inhibitors may be useful for a novel combination chemotherapy. Mol Cancer Ther; 11(10); 2294–300. 2012 AACR.