Phosphofructokinase 1 Glycosylation Regulates Cell Growth and Metabolism
Abstract
Cancer cells must satisfy the metabolic demands of rapid cell growth within a continually changing microenvironment. We demonstrated that the dynamic posttranslational modification of proteins by O-linked β-N-acetylglucosamine (O-GlcNAcylation) is a key metabolic regulator of glucose metabolism. O-GlcNAcylation was induced at serine 529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway, thereby conferring a selective growth advantage on cancer cells. Blocking glycosylation of PFK1 at serine 529 reduced cancer cell proliferation in vitro and impaired tumor formation in vivo. These studies reveal a previously uncharacterized mechanism for the regulation of metabolic pathways in cancer and a possible target for therapeutic intervention.
Additional Information
© 2012 American Association for the Advancement of Science. Received for publication 22 March 2012. Accepted for publication 29 June 2012. We thank P. Qasba for the Y289L GalT construct, R. Abrol for computational modeling advice, R. Diamond for cell cycle analysis, and L. Cantley and M. Vander Heiden for useful discussions. This work was supported by the National Institutes of Health (grant R01 GM084724 to L.C.H-W), the Department of Defense Breast Cancer Research Program (grant W81XWH-10-1-0988 to W.Y), and a Tobacco-Related Disease Research Program Postdoctoral Fellowship (19FT-0078 to W.Y). We also thank Agios Pharmaceuticals for financial support in providing patient tumor and matched tissue samples.Attached Files
Accepted Version - nihms-427904.pdf
Supplemental Material - Yi.W.SM.pdf
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Additional details
- Alternative title
- PFK1 Glycosylation Is a Key Regulator of Cancer Cell Growth and Central Metabolic Pathways
- PMCID
- PMC3534962
- Eprint ID
- 34161
- Resolver ID
- CaltechAUTHORS:20120918-075521218
- R01 GM084724
- NIH
- W81XWH-10-1-0988
- Department of Defense Breast Cancer Research Program
- 19FT-0078
- Tobacco Related Disease Research Program Postdoctoral Fellowship
- Agios Pharmaceutical
- Created
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2012-09-18Created from EPrint's datestamp field
- Updated
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2021-11-09Created from EPrint's last_modified field