title: 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.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Yi
authors.forename: Peter M
authors.initials: PM
authors.lastname: Clark
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Mason
authors.forename: Marie C
authors.initials: MC
authors.lastname: Keenan
authors.forename: Collin
authors.initials: C
authors.lastname: Hill
authors.forename: William A
authors.initials: WA
authors.lastname: Goddard
authors.forename: Eric C
authors.initials: EC
authors.lastname: Peters
authors.forename: Edward M
authors.initials: EM
authors.lastname: Driggers
authors.forename: Linda C
authors.initials: LC
authors.lastname: Hsieh-Wilson
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism; D000215:Acylation; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D006031:Glycosylation; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010427:Pentose Phosphate Pathway; D025501:Phosphofructokinase-1, Liver Type / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D019344:Lactic Acid; D009249:NADP; D000255:Adenosine Triphosphate; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D025501:Phosphofructokinase-1, Liver Type; D005947:Glucose; D000117:Acetylglucosamine