Metastasis of cholangiocarcinoma is promoted by extended high-mannose glycans
| Autor: | Worachart Lert-itthiporn, Michiko Shimoda, Simon S. Park, Sopit Wongkham, Guillaume Luxardi, Khiem Tran, Qiongyu Li, Nobuyuki Matoba, Emanual Michael Maverakis, Laura P. Olney, Fernando A. Fierro, Nathan E. Haigh, Chatchai Phoomak, Carlito B. Lebrilla, Dayoung Park, Gege Xu |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Models Molecular Glycosylation Cell membrane proteins Cell Transformation Cholangiocarcinoma chemistry.chemical_compound Mice 0302 clinical medicine Models 2.1 Biological and endogenous factors Aetiology Neoplasm Metastasis mass spectrometry Cancer Tumor Multidisciplinary Membrane Glycoproteins biology Cell migration Cell biology medicine.anatomical_structure Cell Transformation Neoplastic Phenotype 030220 oncology & carcinogenesis Mannosylation Physical Sciences Female Cell Line 03 medical and health sciences Cell Line Tumor medicine metastasis Animals Humans Cell Proliferation Neoplastic Molecular Glycome Membrane glycoproteins 030104 developmental biology chemistry Membrane protein Cancer cell biology.protein Protein Multimerization Mannose |
| Zdroj: | Proc Natl Acad Sci U S A Proceedings of the National Academy of Sciences of the United States of America, vol 117, iss 14 |
| ISSN: | 1091-6490 |
| Popis: | Membrane-bound oligosaccharides form the interfacial boundary between the cell and its environment, mediating processes such as adhesion and signaling. These structures can undergo dynamic changes in composition and expression based on cell type, external stimuli, and genetic factors. Glycosylation, therefore, is a promising target of therapeutic interventions for presently incurable forms of advanced cancer. Here, we show that cholangiocarcinoma metastasis is characterized by down-regulation of the Golgi α-mannosidase I coding gene MAN1A1, leading to elevation of extended high-mannose glycans with terminating α-1,2-mannose residues. Subsequent reshaping of the glycome by inhibiting α-mannosidase I resulted in significantly higher migratory and invasive capabilities while masking cell surface mannosylation suppressed metastasis-related phenotypes. Exclusive elucidation of differentially expressed membrane glycoproteins and molecular modeling suggested that extended high-mannose glycosylation at the helical domain of transferrin receptor protein 1 promotes conformational changes that improve noncovalent interaction energies and lead to enhancement of cell migration in metastatic cholangiocarcinoma. The results provide support that α-1,2-mannosylated N-glycans present on cancer cell membrane proteins may serve as therapeutic targets for preventing metastasis. |
| Databáze: | OpenAIRE |
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