Sialic Acid Metabolic Engineering: A Potential Strategy for the Neuroblastoma Therapy |
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| Authors: | Vinayaga S Gnanapragassam Kaya Bork Christina E Galuska Sebastian P Galuska Dagobert Glanz Manimozhi Nagasundaram Matthias Bache Dirk Vordermark Guido Kohla Christoph Kannicht Roland Schauer Rüdiger Horstkorte |
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| Institution: | 1. Institute for Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.; 2. Institute of Biochemistry, Faculty of Medicine, University of Giessen, Giessen, Germany.; 3. Clinic of Radiotherapy, University Hospital Halle, Halle (Saale), Germany.; 4. Octapharma R&D, Molecular Biochemistry, Berlin, Germany.; 5. Institute of Biochemistry, University of Kiel, Kiel, Germany.; National Cancer Institute at Frederick, United States of America, |
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| Abstract: | BackgroundSialic 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.MethodsHuman 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.ResultsTreatment 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.ConclusionsMetabolic 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. |
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