Sialic Acid Metabolic Engineering: A Potential Strategy for the Neuroblastoma Therapy

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.

N-Linked Glycan Profiling in Neuroblastoma Cell Lines

“…Within neuroblastoma, monitoring expression of gangliosides GD1b, GT1b, and GQ1b (which display increasing sialylated modification with respect to their “a” versions) has been suggested as a means of stratifying neuroblastoma patients 19 . Additionally, metabolically introducing synthetic Sia precusors has been observed to reduce cell surface polysialylation and overall sialylation activity in SH-SY5Y cells, which in turn leads to a significant reduction in cell migration 28 . The results presented in this paper strengthen the argument of studying glycosylation in neuroblastoma, particularly on associations between increased sialylation in N-linked glycans and disease aggressiveness.…”

Metabolic glycoengineering sensitizes drug-resistant pancreatic cancer cells to tyrosine kinase inhibitors erlotinib and gefitinib

“…The use of a sialic acid precursor with a non-natural acyl group was of interest for two reasons; one was based on a previous report that this class of compounds could sensitize cancer cells towards chemotherapy and radiation treatment. 43 Secondly, azido-modified sugar analogs are capable of labeling cells through click chemistry, 18 , 42 thereby opening new possibilities of not only synergistically combining carbohydrate analogs with EGFR-acting drugs, but to also provide a means to direct additional diagnostic or therapeutic agents to sialylated glycans overexpressed in cancer. 44 , 45 In the current experiments, azido-modified l,3,4- O -Bu 3 ManNAz was more cytotoxic on its own ( Figure 4C ) compared to l,3,4- O -Bu 3 ManNAc, therefore lower concentrations of 12.5 and 25 (μM were used to evaluate synergy ( Figure 4D ).…”

Exploration of the Sialic Acid World

“…Furthermore, ManNPent inhibited polysialylation. 868 The formation of cell membrane N-azidoacetylneuraminic acid (Neu5Az) after the application of per-Oacetylated N-azidoacetylmannosamine (ManNAz) also offers many possibilities for cell biological, including histochemical (see Section 7.4), experiments. 413 Recently, this rapidly growing area of the metabolic glycan labeling strategy was excellently and thoroughly reviewed.…”