Gnanapragassam Vinayaga S, Bork Kaya, Galuska Christina E, Galuska Sebastian P, Glanz Dagobert, Nagasundaram Manimozhi, Bache Matthias, Vordermark Dirk, Kohla Guido, Kannicht Christoph, Schauer Roland, Horstkorte Rüdiger
Institute for Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
Institute of Biochemistry, Faculty of Medicine, University of Giessen, Giessen, Germany.
PLoS One. 2014 Aug 22;9(8):e105403. doi: 10.1371/journal.pone.0105403. eCollection 2014.
Sialic acids (Sia) represent negative-charged terminal sugars on most glycoproteins and glycolipids on the cell surface of vertebrates. Aberrant expression of tumor associated sialylated carbohydrate epitopes significantly increases during onset of cancer. Since Sia contribute towards cell migration ( = metastasis) and to chemo- and radiation resistance. Modulation of cellular Sia concentration and composition poses a challenge especially for neuroblastoma therapy, due to the high heterogeneity and therapeutic resistance of these cells. Here we propose that Metabolic Sia Engineering (MSE) is an effective strategy to reduce neuroblastoma progression and metastasis.
Human neuroblastoma SH-SY5Y cells were treated with synthetic Sia precursors N-propanoyl mannosamine (ManNProp) or N-pentanoyl mannosamine (ManNPent). Total and Polysialic acids (PolySia) were investigated by high performance liquid chromatography. Cell surface polySia were examined by flow-cytometry. Sia precursors treated cells were examined for the migration, invasion and sensitivity towards anticancer drugs and radiation treatment.
Treatment of SH-SY5Y cells with ManNProp or ManNPent (referred as MSE) reduced their cell surface sialylation significantly. We found complete absence of polysialylation after treatment of SH-SY5Y cells with ManNPent. Loss of polysialylation results in a reduction of migration and invasion ability of these cells. Furthermore, radiation of Sia-engineered cells completely abolished their migration. In addition, MSE increases the cytotoxicity of anti-cancer drugs, such as 5-fluorouracil or cisplatin.
Metabolic Sia Engineering (MSE) of neuroblastoma cells using modified Sia precursors reduces their sialylation, metastatic potential and increases their sensitivity towards radiation or chemotherapeutics. Therefore, MSE may serve as an effective method to treat neuroblastoma.
唾液酸（Sia）是脊椎动物细胞表面大多数糖蛋白和糖脂上带负电荷的末端糖。肿瘤相关唾液酸化碳水化合物表位的异常表达在癌症发生过程中显著增加。由于唾液酸有助于细胞迁移（即转移）以及化疗和放疗抗性。调节细胞唾液酸浓度和组成尤其对神经母细胞瘤治疗构成挑战，因为这些细胞具有高度异质性和治疗抗性。在此，我们提出代谢性唾液酸工程（MSE）是一种减少神经母细胞瘤进展和转移的有效策略。
用人神经母细胞瘤SH-SY5Y细胞用合成唾液酸前体N-丙酰甘露糖胺（ManNProp）或N-戊酰甘露糖胺（ManNPent）处理。通过高效液相色谱法研究总唾液酸和多唾液酸（PolySia）。通过流式细胞术检测细胞表面多唾液酸。对用唾液酸前体处理的细胞进行迁移、侵袭以及对抗癌药物和放疗的敏感性检测。
用ManNProp或ManNPent（称为MSE）处理SH-SY5Y细胞可显著降低其细胞表面唾液酸化。我们发现用ManNPent处理SH-SY5Y细胞后完全没有多唾液酸化。多唾液酸化的丧失导致这些细胞的迁移和侵袭能力降低。此外，对经唾液酸工程改造的细胞进行辐射完全消除了它们的迁移能力。此外，MSE增加了抗癌药物如5-氟尿嘧啶或顺铂的细胞毒性。
使用修饰的唾液酸前体对神经母细胞瘤细胞进行代谢性唾液酸工程（MSE）可降低其唾液酸化、转移潜能，并增加其对放疗或化疗的敏感性。因此，MSE可能是一种治疗神经母细胞瘤的有效方法。
