Metabolism Intersects Cell Death at Methylglyoxyl

Abstract

Methylglyoxyl (MG) is a cytotoxic metabolite produced during glycolysis that can react with proteins on cysteine, lysine, and arginine residues, producing advanced glycation end products (AGEs). MG concentrations are increased in diabetic patients. MG is detoxified through the glyoxylase system. Two groups implicate MG in cell death processes involving reactive oxygen species (ROS). Van Herreweghe et al. show that tumor necrosis factor (TNF)-induced nonapoptotic cell death in mouse fibrosarcoma L929 cells, which requires the production of ROS, involves the phosphorylation of glyoxylase I (GLO I) through a cascade that could be blocked by pharmacological inhibition of protein kinase A (PKA). TNF also promoted the formation of a stable, unidentified, but specific AGE. Addition of a GLO I inhibitor before the addition of TNG increased cell survival, but simultaneous addition increased cell morbidity. Pharmacological agents that inhibited GLO I phosphorylation inhibited the production of the AGE and also promoted cell survival. Godbout et al. demonstrated a link between protein kinase Cδ (PKCδ) and MG during cisplatin-stimulated cell death, which also depended on the production of ROS, but was an apoptotic type of cell death. (Cisplatin is an antineoplastic agent.) Cisplatin induced cell death in myeloma U266 cells and was associated with increased ROS and decreased glutathione (GSH), which is a required cofactor for MG detoxification by the glyoxylase system. Addition of MG and cisplatin together increased cell death above that seen with cisplatin alone and stimulated PKCδ activity. The MG- and cisplatin-induced cell death and production of ROS were selectively inhibited if the cells were treated with a PKCδ inhibitor; other MG and cisplatin responses, such as induction of the cell-cycle regulator p21, were unaffected. Finally, MG and cisplatin activated the kinase c-Abl and promoted its association with PKCδ. Inhibition of c-Abl promoted cell death, suggesting that cisplatin and MG also activate a c-Abl cell survival pathway. These two papers implicate the reactive carbonyl MG in two biochemically different types of cell death and suggest that protein kinases may be both upstream (PKA) and downstream (PKCδ) of MG-mediated events. F. Van Herreweghe, J. Mao, F. W. R. Chaplen, J. Grooten, K. Gevaert, J. Vandekerckhove, K. Vancompernolle, Tumor necrosis factor-induced modulation of glyoxalase I activities through phosphorylation by PKA results in cell death and is accompanied by the formation of a specific methylglyoxal-derived AGE. Proc. Natl. Acad. Sci. U.S.A. 99 , 949-954 (2002). [Abstract] [Full Text] J. P. Godbout, J. Pesavento, M. E. Hartman, S. R. Manson, G. G. Freund, Methylglyoxal enhances cisplatin-induced cytotoxicity by activating protein kinase Cδ. Proc. Natl. Acad. Sci. U.S.A. 277 , 2554-2561 (2002). [Abstract] [Full Text]