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O-GlcNAc Glycosylation in Lung Cancer

Institution: California Institute of Technology
Investigator(s): Wen Yi, PH.D
Award Cycle: 2010 (Cycle 19) Grant #: 19FT-0078 Award: $111,397
Subject Area: General Biomedical Science
Award Type: Postdoctoral Fellowship Awards
Abstracts

Initial Award Abstract
Cellular metabolism is significantly altered in rapidly growing cancer cells. Cancer cells consume glucose avidly and produce elevated levels of lactic acid compared to normal tissues. This phenomenon, known as aerobic glycolysis or the “Warburg effect”, has been observed in almost all aggressive cancers including lung cancers. However, how tumor cells obtain this altered metabolism and whether it is essential for cancer development is not well understood. Recently, our laboratory discovered that all of the enzymes involved in the glycolytic pathway are modified by O-linked N-acetylglucosamine (O-GlcNAc), a form of post-translational modification that has been shown to dynamically regulate a number of important cellular signaling pathways, such as gene transcription, cell proliferation, protein degradation and insulin sensing. Increasing evidence has suggested that O-GlcNAc glycosylation acts as a nutrient sensor of the cellular metabolic state. As such, we postulate that O-GlcNAc glycosylation of specific glycolytic enzymes may play a role in regulating glycolysis and contribute to altered metabolic states in lung cancer cells. Consistent with this hypothesis, our preliminary studies indicate that modulating cellular O-GlcNAc levels in lung cancer cells results in significant change of cellular metabolism as exemplified by oxygen consumption rate, lactate production, glycolytic rate, ATP levels, and furthermore, altered activities of several glycolytic enzymes. Thus, our preliminary results identify an exciting new link between the O-GlcNAc modification and cellular metabolism that may have important implications for lung cancer development. In the proposed study, firstly, we will establish the percentage of O-GlcNAc modification on glycolytic enzymes and whether the modification is responsive to the overall O-GlcNAc levels in the cell. Secondly, we will investigate the mechanisms by which O-GlcNAc affects glycolytic enzyme activity. We will identify the actual sites of modification on the enzyme, make mutations that no longer harbor the modification and further examine the effect on cellular metabolism and cell proliferation. Thirdly, we will examine the effect of modulation of O-GlcNAc levels on the activity of another glucose metabolic pathway – pentose phosphate pathway, which is closely associated with the glycolytic pathway. Finally, we will extend our studies from cultured cancer cells to animal studies. We will examine whether modulation of O-GlcNAc levels can affect the ability of lung cancer cells to form tumors in mice. In summary, this proposed research aims at uncovering the link between O-GlcNAc and one of the most fundamental phenotypic hallmarks of lung cancer. The outcome of the proposed research will provide a novel mechanism underlying the altered metabolism in lung cancers. Such finding will likely provide new opportunities to design novel therapeutic intervention to reduce/prevent lung cancer progression and metastasis. Moreover, the findings in this project can be well extended to the study of other forms of cancer. Thus it has a significant impact on the cancer biology.
Publications

Phosphofructokinase 1 Glycosylation Regulates Cell Growth and Metabolism
Periodical: Science Index Medicus:
Authors: Yi, W., Clark, P., Mason, D., Keenan, M., Hill, C., Goddard III, W., Peters, E., Driggers, ART
Yr: 2012 Vol: 337 Nbr: Abs: Pg: 975-980