Sialylation of CCR7 is critical for CCL19-stimulatedproliferation, invasion and anti-anoikis in breast cancer cells

• Main Authors: Mei-lin Su, 蘇美霖
• Other Authors: Wen-Chun Hung
• Format: Others
• Language: en_US
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/64998312648917566117

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.