title: Inhibition of chemokine (C-C motif) receptor 7 sialylation suppresses CCL19-stimulated proliferation, invasion and anti-anoikis.
abstract: Chemokine (C-C motif) receptor 7 (CCR7) is involved in lymph-node homing of naive and regulatory T cells and lymphatic metastasis of cancer cells. Sialic acids comprise a group of monosaccharide units that are added to the terminal position of the oligosaccharide chain of glycoproteins by sialyation. Recent studies suggest that aberrant sialylation of receptor proteins contributes to proliferation, motility, and drug resistance of cancer cells. In this study, we addressed whether CCR7 is a sialylated receptor protein and tried to elucidate the effect of sialylation in the regulation of signal transduction and biological function of CCR7. Our results demonstrated that α-2, 3-sialyltransferase which catalyze sialylation reaction in vivo was overexpressed in breast tumor tissues and cell lines. Lectin blot analysis clearly demonstrated that CCR7 receptor was sialyated in breast cancer cells. Chemokine (C-C motif) ligand 19 (CCL19), the cognate ligand for CCR7, induced the activation of extracellular signal-regulated kinase (ERK) and AKT signaling and increased the expression of cell cycle regulatory proteins and proliferation of breast cancer cells. When cells were pre-treated with a sialyltransferase inhibitor AL10 or sialidase, CCL19-induced cell growth was significantly suppressed. CCL19 also increased invasion and prevented anoikis by up-regulating pro-survival proteins Bcl-2 and Bcl-xL. Inhibition of sialylation by AL10 totally abolished these effects. Finally, we showed that AL10 inhibited tumorigenicity of breast cancer in experimental animals. Taken together, we demonstrate for the first time that CCR7 receptor is a sialylated protein and sialylation is important for the paracrine stimulation by its endogenous ligand CCL19. In addition, inhibition of aberrant sialylation of CCR7 suppresses proliferation and invasion and triggers anoikis in breast cancer cells. Targeting of sialylation enzymes may be a novel strategy for breast cancer treatment.
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan, Republic of China.
authors.forename: Mei-Lin
authors.initials: ML
authors.lastname: Su
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan, Republic of China.
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Chang
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan, Republic of China.
authors.forename: Chi-Hsiang
authors.initials: CH
authors.lastname: Chiang
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, Taiwan, Republic of China.
authors.forename: Han-Chen
authors.initials: HC
authors.lastname: Chang
authors.affiliation: Department of Surgery, College of Medicine, Kaohsiung Medical University, and Department of Surgery, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan, Republic of China; Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, Republic of China.
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Hou
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, Taiwan, Republic of China.
authors.forename: Wen-Shan
authors.initials: WS
authors.lastname: Li
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan, Republic of China; National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan, Republic of China.
authors.forename: Wen-Chun
authors.initials: WC
authors.lastname: Hung
mesh_terms: D000818:Animals; D023102:Anoikis / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D054415:Chemokine CCL19 / Q000378:metabolism* / Q000494:pharmacology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D064593:Heterografts; D006801:Humans; D012323:RNA Processing, Post-Transcriptional; D054400:Receptors, CCR7 / Q000378:metabolism*; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
chemical_list: D054415:Chemokine CCL19; D054400:Receptors, CCR7; D019938:Cyclin D1; D012799:Sialyltransferases; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase; C000722087:ST3GAL1 protein, human