Department of Chemical and Biomolecular Engineering, The Johns Hopkins Medical Institution, Baltimore, MD, USA.
Mol Cell Proteomics. 2012 Jul;11(7):M112.017558. doi: 10.1074/mcp.M112.017558. Epub 2012 Mar 28.
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.
本研究报告了一项胰腺癌细胞的全球糖蛋白组学分析，该分析描述了唾液酸生物合成途径的通量如何选择性地调节细胞蛋白中存在的一组 N-糖基化位点。这些结果表明，唾液糖蛋白模式不是由生物合成酶的转录或 N-聚糖序列的可用性决定的；相反，唾液酸途径的大量代谢通量具有显著增加某些唾液糖蛋白丰度的能力，而对其他糖蛋白的影响最小。具体而言，通过质谱和生物信息学方法鉴定的 82 种糖蛋白中，约 31%的糖蛋白的唾液酸化没有变化，约 29%的糖蛋白的唾液酸化略有增加，而约 40%的糖蛋白的唾液酸化增加了两倍以上。特定糖蛋白的唾液酸化增加导致 SW1990 胰腺癌细胞的粘附特性发生变化（例如，在生理流动下增加了 CD44 介导的对选择素的粘附，以及在胶原蛋白和纤维连接蛋白上增强了整合素介导的细胞迁移）。这些结果表明，癌细胞可以通过控制代谢通量来影响与转移转化相关的蛋白质的唾液酸化，从而变得更具侵袭性。
