Rahul Bhattarcharya

Johns Hopkins University, Baltimore, Maryland, United States

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Publications (2)6.56 Total impact

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    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.
    No preview · Article · Mar 2012 · Molecular & Cellular Proteomics
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    ABSTRACT: Sialic acids are located at the termini of mammalian cell-surface glycostructures and play pivotal rolesin nature. They are mostly found in eukaryote cells and because of their negative charge and locationat the cell surface, mediate cell recognition and adhesion. In many cancers, sialylated structures suchas the sialyl Lewis antigens are over expressed and are correlated with malignacy. In this work we demonstrate that a high flux non-natural sugar analog can modulate sialylation making a pancreatic cancer cell line more migratory when tested using in vitro environments that mimic certain steps of the metastatic process. We demonstrated that surface expression of cancer-associated sialyl carbohydrate determinants such as sialyl Lewis X and sialyl Lewis A increases with increased flux through the sialicacid pathway while other epitopes, including Lewis X and RCA-lectin ligands decrease, suggesting that the overall number of glycoconjugates remains unchanged and only the level of sialylation is affected by increased metabolic flux. Glycoproteomic experiments demonstrated that the increased flux through the sialic acid pathway, which increases the intracellular pool of this sugar, inturn modulates the sialylation of individual glycoconjugates. Functional studies demonstrated significant differences in the biophysical properties of analog-treated cells relative to untreated cells; specific examples include enhanced CD44-selectin binding under flow as well as increased migrationon integrin and fibronectin substrates. These results indicate that cancer cells may adopt a strategy ofincreasing early steps of sialylation to modulate cell adhesion molecules involved in metastasis to become more aggressively malignant.
    No preview · Conference Paper · Oct 2011