Sialyltransferases (STs), which catalyze the sialylation reaction by
adding sialic acids to the terminal positions of oligosaccharide of
glycoproteins and glycolipids, are over-expressed in cancer cells
and associated with cancer metastasis. Until now, ST inhibitors
are not applicable for clinical use because of poor cell
permeability, although showing potent effect in vitro. In this study,
we synthesize a lithocholic acid-based ST inhibitor AL10 and test
its anti-metastatic effect. Overexpression of £\-2,3-ST is found in
highly metastatic A549 and CL1-5 lung cancer cells. Confocal
microscopy demonstrates that AL10 is cell permeable and may
attenuate total sialylation on cell surface. AL10 has no cytotoxicity
but inhibits adhesion, migration, actin polymerization and invasion
of A549 and CL1-5 cells in vitro. Inhibition of adhesion and
migration by AL10 is associated with reduced sialylation of beta1
integrin. In addition, activation of the beta1 integrin downstream
signaling molecule focal adhesion kinase is also attenuated. More
importantly, AL10 suppresses lung metastasis in vivo and this
effect may be linked with reduced sialylation of the chemokine
receptor CXCR4 which has been found to play a critical role in
organ-specific metastasis. Serum biochemical assay indicates that
AL10 does not affect liver and kidney functions of experimental
animals. Taken together, we conclude that AL10 is an effective
sialyltransferase inhibitor and exerts anti-metastatic effect in vivo
via suppression of sialylation of beta1 integrin and CXCR4.
| Identifer | oai:union.ndltd.org:NSYSU/oai:NSYSU:etd-0811109-180108 |
| Date | 11 August 2009 |
| Creators | Chiang, Chi-hsiang |
| Contributors | Hui-Chiu Chang, Wen-Chun Hung, Long-Sen Chang |
| Publisher | NSYSU |
| Source Sets | NSYSU Electronic Thesis and Dissertation Archive |
| Language | Cholon |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0811109-180108 |
| Rights | campus_withheld, Copyright information available at source archive |
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