Abstract
Methylglyoxal is an essential component in glycolysis and is known to be 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 of GLO1 enhances sensitivity to the promising anticancer agent TRAIL in malignant 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 and DR5. 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-κB 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.
Highlights
Glyoxalase I (GLO1) is known to metabolize and inactivate methylglyoxal, one of the side products of glycolysis [1, 2]
To elucidate the underlying mechanisms by which methylglyoxal enhanced TRAIL-induced apoptosis, we examined the changes of protein expression by methylglyoxal in SW480 cells
These results suggest that the sensitization of TRAIL-induced apoptosis by methylglyoxal is relevant to the inhibition of antiapoptotic proteins
Summary
Glyoxalase I (GLO1) is known to metabolize and inactivate methylglyoxal, one of the side products of glycolysis [1, 2]. Overexpression of GLO1 is observed in several types of malignant tumors, such as colon, breast, ovarian, and prostate cancer [3,4,5,6,7,8]. GLO1 is overexpressed in the more aggressive ovarian cancer or leukemia cells resistant to apoptosis caused by antitumor agents [9,10,11]. Such findings suggest that GLO1 inhibitors may be potent chemotherapeutic agents causing an Authors' Affiliations: Departments of 1Molecular-Targeting Cancer Prevention, 2 Gastroenterology, and 3 Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan; and 4Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.