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Researchers have found that glycosylation of an important metabolic and regulatory enzyme helps cancer cells grow and thrive and that blocking the process reduces cancer growth and impairs tumor formation. The discovery of this previously unknown cancer-promoting mechanism points to a new drug target that could be exploited to fight cancer.
Modification of proteins with oxygen-linked β-N-acetylglucosamine (O-GlcNAc) groups helps regulate nutrient metabolism in cells, including cancerous ones. But how the process works has not been well understood. Now, carbohydrate chemist Linda C. Hsieh-Wilson and coworkers at Caltech, the Genomics Institute of the Novartis Research Foundation, and Agios Pharmaceuticals have found that one major interaction responsible for this regulatory process is the O-GlcNAcylation of a serine residue at a regulatory site in the metabolic enzyme phosphofructokinase 1 (PFK1).
Hsieh-Wilson discussed the work last week at the American Chemical Society national meeting in Philadelphia during a Division of Biological Chemistry symposium on 50 years of research support by the National Institute of General Medical Sciences (C&EN, Aug. 20, page 20). Her team also reports the findings in Science (DOI: 10.1126/science.1222278).
Gerald W. Hart of Johns Hopkins University School of Medicine, whose group discovered O-GlcNAcylation in the early 1980s, told C&EN that “O-GlcNAcylation has been found to be elevated in every cancer cell type examined to date, but its effects on the mechanisms underlying cancer cell etiology have yet to be elucidated. This paper could be a major breakthrough in our understanding of the regulation of cancer cell metabolism and likely represents a totally unexpected avenue for therapeutic development.”
Hsieh-Wilson and coworkers found that PFK1 is modified by O-GlcNAc under conditions of rapid tumor growth and that the modification inhibits PFK1 activity by blocking a binding site of an allosteric activator. “This results in a rerouting of metabolic flux toward the production of metabolites essential for DNA biosynthesis as well as antioxidants important for combating reactive-oxygen-species-mediated cell death,” Hsieh-Wilson said at the symposium. These processes support tumor growth. Interfering with PFK1 glycosylation thus represents a new anticancer strategy.
For their work, Hsieh-Wilson and coworkers used chemoenzymatic detection of sugars, computational modeling, and functional studies. The research “would not have been possible without the development of chemical tools for the detection and study of O-GlcNAcylation as well as computational methods for understanding the effects of the modification on protein structure,” she said.
O-GlcNAcylation expert Chad Slawson of the University of Kansas Medical Center told C&EN that the study represents “a major finding in the O-GlcNAc field and more significantly demonstrates the importance of posttranslational modifications besides phosphorylation in regulating protein function.”
The Hsieh-Wilson study puts O-GlcNAcylation “front and center in regulating cancer metabolism,” added oncogenic signaling specialist Mauricio J. Reginato of Drexel University College of Medicine.
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