title: Metabolic flux increases glycoprotein sialylation: implications for cell adhesion and cancer metastasis.
abstract: This study reports a global glycoproteomic analysis of pancreatic cancer cells that describes how flux through the sialic acid biosynthetic pathway selectively modulates a subset of N-glycosylation sites found within cellular proteins. These results provide evidence that sialoglycoprotein patterns are not determined exclusively by the transcription of biosynthetic enzymes or the availability of N-glycan sequons; instead, bulk metabolic flux through the sialic acid pathway has a remarkable ability to increase the abundance of certain sialoglycoproteins while having a minimal impact on others. Specifically, of 82 glycoproteins identified through a mass spectrometry and bioinformatics approach, ≈ 31% showed no change in sialylation, ≈ 29% exhibited a modest increase, whereas ≈ 40% experienced an increase of greater than twofold. Increased sialylation of specific glycoproteins resulted in changes to the adhesive properties of SW1990 pancreatic cancer cells (e.g. increased CD44-mediated adhesion to selectins under physiological flow and enhanced integrin-mediated cell mobility on collagen and fibronectin). These results indicate that cancer cells can become more aggressively malignant by controlling the sialylation of proteins implicated in metastatic transformation via metabolic flux.
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Johns Hopkins Medical Institution, Baltimore, MD, USA.
authors.forename: Ruben T
authors.initials: RT
authors.lastname: Almaraz
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.forename: Rahul
authors.initials: R
authors.lastname: Bhattarcharya
authors.forename: Elaine
authors.initials: E
authors.lastname: Tan
authors.forename: Shih-Hsun
authors.initials: SH
authors.lastname: Chen
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Dallas
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Konstantopoulos
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Yarema
mesh_terms: D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D039503:Integrin alpha6 / Q000378:metabolism; D008958:Models, Molecular; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D019087:Selectins / Q000378:metabolism; D012794:Sialic Acids / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D053719:Tandem Mass Spectrometry
chemical_list: D005353:Fibronectins; D018960:Hyaluronan Receptors; D039503:Integrin alpha6; D009363:Neoplasm Proteins; D019087:Selectins; D012794:Sialic Acids; D012795:Sialoglycoproteins; D003094:Collagen