| Summary: | 碩士 === 國立中山大學 === 生物醫學研究所 === 100 === Sialylation is catalyzed by sialyltransferases (STs) that adding sialic acids to the
terminal positions of oligosaccharide of glycoproteins and glycolipids. This process is
frequently enhanced in cancer and is associated with increased cancer metastasis. Recent
studies demonstrated that over-expression of ST3Gal-I promotes mammary
tumorigenesis. In our experiments, we also find overexpression of α-2,3-ST in breast
cancer cells. We previously synthesized a lithocholic acid-based ST inhibitor AL10 and
demonstrated its anti-metastatic effect in vitro and in vivo. Our results showed that
AL10 is an effective sialyltransferase inhibitor and exerts anti-metastatic effect in vivo
via suppression of sialylation of beta1 integrin and CXCR4. Breast cancer cells
expressing high level of chemokine receptors CXCR4 and CCR7 are prone to exhibit
lymphatic metastasis because their cognate ligands CCL19, CCL21 and SDF-1 are
continuously expressed by lymphatic endothelial cells. In this study, we demonstrate
that AL10 can inhibit invasion, proliferation and induce anoikis of
α-2,3-ST-overexpressing MDA-MB231 human breast cancer cells. Our results indicate
that inhibition of CCL19-induced invasion and CCL19-reduced anoikis by AL10 are
associated with reduced sialylation of CCR7 and attenuated activation of the
downstream signaling mediator ERK and p38. In addition, AL10 can inhibit
proliferation by reducing activation of AKT via CCR7 sialylation independent pathway
and p-38 via CCR7 sialylation dependent pathway which results in ubiquitin-dependent
cyclin D1 degradation. Taken together, we conclude that sialylation of CCR7 is critical
for CCL19-stimulated proliferation, invasion and anti-anoikis in breast cancer cells.
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