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1
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Cai Z, Isaji T, Liang C, Fukuda T, Zhang D, Gu J. Fucosyltransferase 4 upregulates P-gp expression for chemoresistance via NF-κB signaling pathway. Biochim Biophys Acta Gen Subj 2025; 1869:130753. [PMID: 39725242 DOI: 10.1016/j.bbagen.2024.130753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 12/19/2024] [Accepted: 12/22/2024] [Indexed: 12/28/2024]
Abstract
BACKGROUND Multidrug resistance (MDR) poses a significant obstacle to developing chemotherapeutic treatments. In previous studies using a traditional model of adriamycin resistance (ADR) with K562 cells, we demonstrated that N-acetylglucosaminyltransferase III (GnT-III) expression negatively regulates chemoresistance. Additionally, we observed that fucosylation levels were increased in the ADR cells. METHOD Fucosylation levels were determined using lectin blot, western blot, and flow cytometry. Gene expression levels were analyzed via qPCR. We generated a FUT4 knockout (KO) ADR cell line using CRISPR/Cas9 technology. Cytotoxicity and drug efflux assays were conducted to evaluate chemotherapy tolerance. RESULTS The expression levels of FUT4 and its products, the LeX antigens, were significantly upregulated in the ADR cells compared to the parental K562 cells. The FUT4 KO reduced the elevated levels of P-glycoprotein (P-gp) found in ADR cells and exhibited increased sensitivity to chemotherapeutic drugs. Furthermore, restoring FUT4 expression in the KO cells effectively reversed P-gp expression, drug efflux, and chemoresistance. Given the critical role of the NF-κB pathway in P-gp expression, we investigated NF-κB signaling and found that the phosphorylation levels of p65 were significantly increased in the ADR cells but were downregulated in the FUT4 KO cells. Furthermore, the restoration of FUT4 rescued the phosphorylation levels of p65. CONCLUSIONS FUT4 specifically upregulates P-gp expression related to chemoresistance through the NF-κB signaling pathway. GENERAL SIGNIFICANCE This study highlights the importance of FUT4 in chemoresistance and suggests it may serve as a promising target for combating MDR.
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Affiliation(s)
- Zixuan Cai
- Division of Regulatory Glycobiology, Graduate School of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Japan
| | - Tomoya Isaji
- Division of Regulatory Glycobiology, Graduate School of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Japan; Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan
| | - Caixia Liang
- Division of Regulatory Glycobiology, Graduate School of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Japan; Medical Research Center, Affiliated Hospital 2 of Nantong University, Nantong, Jiangsu Province 226001, China
| | - Tomohiko Fukuda
- Division of Regulatory Glycobiology, Graduate School of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Japan; Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan
| | - Dongmei Zhang
- Medical Research Center, Affiliated Hospital 2 of Nantong University, Nantong, Jiangsu Province 226001, China
| | - Jianguo Gu
- Division of Regulatory Glycobiology, Graduate School of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Japan; Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan.
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Hou Y, Ye J, Qin K, Cui LA, Chung S, Chapla DG, Wang W, Shi Y, Chen M, Moremen KW, Sackstein R, Wu P. Enforced E-selectin ligand installation enhances homing and efficacy of adoptively transferred T cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.12.632650. [PMID: 39868097 PMCID: PMC11761414 DOI: 10.1101/2025.01.12.632650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Adoptive T-cell transfer has revolutionized the treatment of hematological malignancies. However, this approach has had very limited success in treating solid tumors, largely due to inadequate infiltration of vascularly administered T cells at tumor sites. The shear-resistant interaction between endothelial E-selectin and its cognate ligand expressed on leukocytes, sialyl Lewis X (sLeX), is an essential prerequisite for extravasation of circulating leukocytes. Here, we report that enforced E-selectin ligand expression (enforced sLeX display) on antigen-specific T cells can be achieved by fucosylating cells via cell surface treatment with the human α1-3-fucosyltransferase, FUT6 ("exofucosylation"), or via Golgi-targeted FUT6 overexpression ("Golgi-fucosylation"). However, despite comparable E-selectin binding, only sLeX-modified T cells engendered by exofucosylation, not by Golgi-fucosylation, exhibited enhanced parenchymal infiltration of target malignant sites. This heightened homing yielded significantly improved therapeutic efficacy in various murine syngeneic and xenograft cancer models, including subcutaneous solid tumors, lymphoma and leukemia, as well as lung and bone marrow metastases. Therefore, exofucosylation represents a promising strategy to improve the efficacy of adoptive T-cell therapy, particularly in the treatment of solid tumors and metastatic disease.
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Affiliation(s)
- Yingqin Hou
- Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA 92037, United States
| | - Jinfeng Ye
- Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA 92037, United States
| | - Ke Qin
- Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA 92037, United States
| | - Leigh-Ann Cui
- Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA 92037, United States
| | - Shereen Chung
- Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA 92037, United States
| | | | - Wenjian Wang
- Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA 92037, United States
| | - Yujie Shi
- Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA 92037, United States
| | - Mingkuan Chen
- Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA 92037, United States
| | - Kelley. W. Moremen
- Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, United States
| | - Robert Sackstein
- Department of Translational Medicine & Translational Glycobiology Institute, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, United States
| | - Peng Wu
- Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA 92037, United States
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3
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Feng H, Liang L, Deng W, Gao J, Li X, Guan F. Sialyl Lewis X decorated integrin α3 on small extracellular vesicles promotes metastasis of bladder cancer via enhancing vascular permeability. Angiogenesis 2024; 27:883-901. [PMID: 39222273 DOI: 10.1007/s10456-024-09947-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024]
Abstract
The permeability of blood vessels plays a crucial role in the spread of cancer cells, facilitating their metastasis at distant sites. Small extracellular vesicles (sEVs) are known to contribute to the metastasis of various cancers by crossing the blood vessel wall. However, the role of abnormal glycoconjugates on sEVs in tumor blood vessels remains unclear. Our study found elevated levels of fucosyltransferase VII (FUT7) and its product sialyl Lewis X (sLeX) in muscle-invasive bladder cancer (BLCA), with high levels of sLeX promoting the growth and invasion of BLCA cells. Further investigation revealed that sLeX was enriched in sEVs derived from BLCA. sLeX-decorated sEVs increased blood vessel permeability by disrupting the tight junctions of human umbilical vein endothelial cells (HUVECs). Using the glycoproteomics approach, we identified integrin α3 (ITGA3) as a sLeX-bearing glycoprotein in BLCA cells and their sEVs. Mechanically, sLeX modification stabilized ITGA3 by preventing its degradation in lysosomes. sEVs carrying sLeX-modified ITGA3 can be effectively internalized by HUVECs, leading to a decrease in the expression of tight junction protein. Conversely, silencing ITGA3 in sLeX-decorated sEVs restored tight junction proteins and reduced blood vessel permeability by inhibiting the MAPK pathway. Moreover, sLeX-modification of ITGA3 at Asn 265 in HUVECs promoted occludin dephosphorylation at Ser/Thr residues, followed by inducing its importin α1-mediated nuclear translocation, which resulted in the disruption of tight junctions. Our findings suggest a potential strategy for disrupting the formation of a metastatic microenvironment and preventing the spread of malignant bladder cancer.
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Affiliation(s)
- Hui Feng
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, 710069, People's Republic of China
| | - Liang Liang
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, People's Republic of China
| | - Wenli Deng
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, 710069, People's Republic of China
| | - Jiaojiao Gao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, 710069, People's Republic of China
| | - Xiang Li
- Institute of Hematology, School of Medicine, Northwest University, Xi'an, 710069, People's Republic of China
| | - Feng Guan
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, 710069, People's Republic of China.
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4
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Solomon J, Gutierrez-Reyes CD, Chávez-Reyes J, Onigbinde S, Marichal-Cancino BA, López-Lariz CH, Beck M, Mechref Y. Neuroglycome alterations of hippocampus and prefrontal cortex of juvenile rats chronically exposed to glyphosate-based herbicide. Front Neurosci 2024; 18:1442772. [PMID: 39234181 PMCID: PMC11371619 DOI: 10.3389/fnins.2024.1442772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 07/19/2024] [Indexed: 09/06/2024] Open
Abstract
Introduction Glyphosate-based herbicides (GBHs) have been shown to have significant neurotoxic effects, affecting both the structure and function of the brain, and potentially contributing to the development of neurodegenerative disorders. Despite the known importance of glycosylation in disease progression, the glycome profile of systems exposed to GBH has not been thoroughly investigated. Methods In this study, we conducted a comprehensive glycomic profiling using LC-MS/MS, on the hippocampus and prefrontal cortex (PFC) of juvenile rats exposed to GBH orally, aiming to identify glyco-signature aberrations after herbicide exposure. Results We observed changes in the glycome profile, particularly in fucosylated, high mannose, and sialofucosylated N-glycans, which may be triggered by GBH exposure. Moreover, we found major significant differences in the N-glycan profiles between the GBH-exposed group and the control group when analyzing each gender independently, in contrast to the analysis that included both genders. Notably, gender differences in the behavioral test of object recognition showed a decreased performance in female animals exposed to GBH compared to controls (p < 0.05), while normal behavior was recorded in GBH-exposed male rats (p > 0.05). Conclusion These findings suggest that glycans may play a role in the neurotoxic effect caused by GBH. The result suggests that gender variation may influence the response to GBH exposure, with potential implications for disease progression and specifically the neurotoxic effects of GBHs. Understanding these gender-specific responses could enhance knowledge of the mechanisms underlying GBH-induced toxicity and its impact on brain health. Overall, our study represents the first detailed analysis of N-glycome profiles in the hippocampus and PFC of rats chronically exposed to GBH. The observed alterations in the expression of N-glycan structures suggest a potential neurotoxic effect associated with chronic GBH exposure, highlighting the importance of further research in this area.
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Affiliation(s)
- Joy Solomon
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States
| | | | - Jesús Chávez-Reyes
- Department of Physiology and Pharmacology, Center of Basic Sciences, Universidad Autonoma de Aguascalientes, Aguascalientes, Mexico
| | - Sherifdeen Onigbinde
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States
| | - Bruno A Marichal-Cancino
- Department of Physiology and Pharmacology, Center of Basic Sciences, Universidad Autonoma de Aguascalientes, Aguascalientes, Mexico
| | - Carlos H López-Lariz
- Department of Physiology and Pharmacology, Center of Basic Sciences, Universidad Autonoma de Aguascalientes, Aguascalientes, Mexico
| | - Mia Beck
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States
| | - Yehia Mechref
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States
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5
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Hu D, Kobayashi N, Ohki R. FUCA1: An Underexplored p53 Target Gene Linking Glycosylation and Cancer Progression. Cancers (Basel) 2024; 16:2753. [PMID: 39123480 PMCID: PMC11311387 DOI: 10.3390/cancers16152753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 07/26/2024] [Accepted: 07/31/2024] [Indexed: 08/12/2024] Open
Abstract
Cancer is a difficult-to-cure disease with high worldwide incidence and mortality, in large part due to drug resistance and disease relapse. Glycosylation, which is a common modification of cellular biomolecules, was discovered decades ago and has been of interest in cancer research due to its ability to influence cellular function and to promote carcinogenesis. A variety of glycosylation types and structures regulate the function of biomolecules and are potential targets for investigating and treating cancer. The link between glycosylation and carcinogenesis has been more recently revealed by the role of p53 in energy metabolism, including the p53 target gene alpha-L-fucosidase 1 (FUCA1), which plays an essential role in fucosylation. In this review, we summarize roles of glycan structures and glycosylation-related enzymes to cancer development. The interplay between glycosylation and tumor microenvironmental factors is also discussed, together with involvement of glycosylation in well-characterized cancer-promoting mechanisms, such as the epidermal growth factor receptor (EGFR), phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and p53-mediated pathways. Glycan structures also modulate cell-matrix interactions, cell-cell adhesion as well as cell migration and settlement, dysfunction of which can contribute to cancer. Thus, further investigation of the mechanistic relationships among glycosylation, related enzymes and cancer progression may provide insights into potential novel cancer treatments.
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Affiliation(s)
- Die Hu
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada;
| | - Naoya Kobayashi
- Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan;
- Department of NCC Cancer Science, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Rieko Ohki
- Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan;
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6
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Zhang J, Huang S, Zhu Z, Gatt A, Liu J. E-selectin in vascular pathophysiology. Front Immunol 2024; 15:1401399. [PMID: 39100681 PMCID: PMC11294169 DOI: 10.3389/fimmu.2024.1401399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 07/05/2024] [Indexed: 08/06/2024] Open
Abstract
Selectins are a group of Ca2+-dependent, transmembrane type I glycoproteins which attract cell adhesion and migration. E-selectin is exclusively expressed in endothelial cells, and its expression is strongly enhanced upon activation by pro-inflammatory cytokines. The interaction of E-selectin with its ligands on circulating leukocytes captures and slows them down, further facilitating integrin activation, firm adhesion to endothelial cells and transmigration to tissues. Oxidative stress induces endothelial cell injury, leading to aberrant expression of E-selectin. In addition, the elevated level of E-selectin is positively related to high risk of inflammation. Dysregulation of E-selectin has been found in several pathological conditions including acute kidney injury (AKI), pulmonary diseases, hepatic pathology, Venous thromboembolism (VTE). Deletion of the E-selectin gene in mice somewhat ameliorates these complications. In this review, we describe the mechanisms regulating E-selectin expression, the interaction of E-selectin with its ligands, the E-selectin physiological and pathophysiological roles, and the therapeutical potential of targeting E-selectin.
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Affiliation(s)
- Jinjin Zhang
- Department of Laboratory Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
- Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
| | - Shengshi Huang
- Institute of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Shandong Provincial Key Medical and Health Laboratory of Translational Medicine in Microvascular Aging, Jinan, China
| | - Zhiying Zhu
- Department of Laboratory Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
| | - Alex Gatt
- Department of Pathology, Faculty of Medicine and Surgery, University of Malta, Msida, Malta
- Haematology Laboratory, Department of Pathology, Mater Dei Hospital, Msida, Malta
| | - Ju Liu
- Department of Laboratory Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
- Institute of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Shandong Provincial Key Medical and Health Laboratory of Translational Medicine in Microvascular Aging, Jinan, China
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7
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Gilormini PA, Thota VN, Fers-Lidou A, Ashmus RA, Nodwell M, Brockerman J, Kuo CW, Wang Y, Gray TE, Nitin, McDonagh AW, Guu SY, Ertunc N, Yeo D, Zandberg WF, Khoo KH, Britton R, Vocadlo DJ. A metabolic inhibitor blocks cellular fucosylation and enables production of afucosylated antibodies. Proc Natl Acad Sci U S A 2024; 121:e2314026121. [PMID: 38917011 PMCID: PMC11228515 DOI: 10.1073/pnas.2314026121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 05/20/2024] [Indexed: 06/27/2024] Open
Abstract
The fucosylation of glycoproteins regulates diverse physiological processes. Inhibitors that can control cellular levels of protein fucosylation have consequently emerged as being of high interest. One area where inhibitors of fucosylation have gained significant attention is in the production of afucosylated antibodies, which exhibit superior antibody-dependent cell cytotoxicity as compared to their fucosylated counterparts. Here, we describe β-carbafucose, a fucose derivative in which the endocyclic ring oxygen is replaced by a methylene group, and show that it acts as a potent metabolic inhibitor within cells to antagonize protein fucosylation. β-carbafucose is assimilated by the fucose salvage pathway to form GDP-carbafucose which, due to its being unable to form the oxocarbenium ion-like transition states used by fucosyltransferases, is an incompetent substrate for these enzymes. β-carbafucose treatment of a CHO cell line used for high-level production of the therapeutic antibody Herceptin leads to dose-dependent reductions in core fucosylation without affecting cell growth or antibody production. Mass spectrometry analyses of the intact antibody and N-glycans show that β-carbafucose is not incorporated into the antibody N-glycans at detectable levels. We expect that β-carbafucose will serve as a useful research tool for the community and may find immediate application for the rapid production of afucosylated antibodies for therapeutic purposes.
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Affiliation(s)
| | | | - Anthony Fers-Lidou
- Department of Chemistry, Simon Fraser University, Burnaby, BCV5A 1S6, Canada
| | - Roger A. Ashmus
- Department of Chemistry, Simon Fraser University, Burnaby, BCV5A 1S6, Canada
| | - Matthew Nodwell
- Department of Chemistry, Simon Fraser University, Burnaby, BCV5A 1S6, Canada
| | - Jacob Brockerman
- Department of Chemistry, Simon Fraser University, Burnaby, BCV5A 1S6, Canada
| | - Chu-Wei Kuo
- Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei11529, Taiwan
| | - Yang Wang
- Department of Chemistry, Simon Fraser University, Burnaby, BCV5A 1S6, Canada
| | - Taylor E. Gray
- Department of Chemistry, University of British Columbia, Kelowna, BCV1V 1V7, Canada
| | - Nitin
- Department of Chemistry, University of British Columbia, Kelowna, BCV1V 1V7, Canada
| | - Anthony W. McDonagh
- Department of Chemistry, Simon Fraser University, Burnaby, BCV5A 1S6, Canada
| | - Shih-Yun Guu
- Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei11529, Taiwan
| | - Nursah Ertunc
- Department of Chemistry, Simon Fraser University, Burnaby, BCV5A 1S6, Canada
| | | | - Wesley F. Zandberg
- Department of Chemistry, University of British Columbia, Kelowna, BCV1V 1V7, Canada
| | - Kay-Hooi Khoo
- Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei11529, Taiwan
| | - Robert Britton
- Department of Chemistry, Simon Fraser University, Burnaby, BCV5A 1S6, Canada
| | - David J. Vocadlo
- Department of Chemistry, Simon Fraser University, Burnaby, BCV5A 1S6, Canada
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BCV5A 1S6, Canada
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8
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Uy GL, DeAngelo DJ, Lozier JN, Fisher DM, Jonas BA, Magnani JL, Becker PS, Lazarus HM, Winkler IG. Targeting hematologic malignancies by inhibiting E-selectin: A sweet spot for AML therapy? Blood Rev 2024; 65:101184. [PMID: 38493006 PMCID: PMC11051645 DOI: 10.1016/j.blre.2024.101184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 02/06/2024] [Accepted: 02/26/2024] [Indexed: 03/18/2024]
Abstract
E-selectin, a cytoadhesive glycoprotein, is expressed on venular endothelial cells and mediates leukocyte localization to inflamed endothelium, the first step in inflammatory cell extravasation into tissue. Constitutive marrow endothelial E-selectin expression also supports bone marrow hematopoiesis via NF-κB-mediated signaling. Correspondingly, E-selectin interaction with E-selectin ligand (sialyl Lewisx) on acute myeloid leukemia (AML) cells leads to chemotherapy resistance in vivo. Uproleselan (GMI-1271) is a carbohydrate analog of sialyl Lewisx that blocks E-selectin binding. A Phase 2 trial of MEC chemotherapy combined with uproleselan for relapsed/refractory AML showed a median overall survival of 8.8 months and low (2%) rates of severe oral mucositis. Clinical trials seek to confirm activity in AML and mitigation of neutrophil-mediated adverse events (mucositis and diarrhea) after intensive chemotherapy. In this review we summarize E-selectin biology and the rationale for uproleselan in combination with other therapies for hematologic malignancies. We also describe uproleselan pharmacology and ongoing clinical trials.
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Affiliation(s)
- Geoffrey L Uy
- Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA
| | - Daniel J DeAngelo
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | | | | | - Brian A Jonas
- Department of Internal Medicine, Division of Malignant Hematology/Cellular Therapy and Transplantation, University of California Davis, Davis, CA, USA
| | | | - Pamela S Becker
- Leukemia Division, Department of Hematology and Hematopoietic Cell Transplantation, Department of Hematologic Malignancies Translational Science, City of Hope National Medical Center, Duarte, CA, USA
| | - Hillard M Lazarus
- Department of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Ingrid G Winkler
- Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, Woolloongabba, QLD, Australia
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9
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Atashi M, Reyes CDG, Sandilya V, Purba W, Ahmadi P, Hakim MA, Kobeissy F, Plazzi G, Moresco M, Lanuzza B, Ferri R, Mechref Y. LC-MS/MS Quantitation of HILIC-Enriched N-glycopeptides Derived from Low-Abundance Serum Glycoproteins in Patients with Narcolepsy Type 1. Biomolecules 2023; 13:1589. [PMID: 38002271 PMCID: PMC10669497 DOI: 10.3390/biom13111589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 10/18/2023] [Accepted: 10/20/2023] [Indexed: 11/26/2023] Open
Abstract
Glycoproteomic analysis is always challenging because of low abundance and complex site-specific heterogeneity. Glycoproteins are involved in various biological processes such as cell signaling, adhesion, and cell-cell communication and may serve as potential biomarkers when analyzing different diseases. Here, we investigate glycoproteins in narcolepsy type 1 (NT1) disease, a form of narcolepsy characterized by cataplexy-the sudden onset of muscle paralysis that is typically triggered by intense emotions. In this study, 27 human blood serum samples were analyzed, 16 from NT1 patients and 11 from healthy individuals serving as controls. We quantified hydrophilic interaction liquid chromatography (HILIC)-enriched glycopeptides from low-abundance serum samples of controls and NT1 patients via LC-MS/MS. Twenty-eight unique N-glycopeptides showed significant changes between the two studied groups. The sialylated N-glycopeptide structures LPTQNITFQTESSVAEQEAEFQSPK HexNAc6, Hex3, Neu5Ac2 (derived from the ITIH4 protein) and the structure IVLDPSGSMNIYLVLDGSDSIGASNFTGAK HexNAc5, Hex4, Fuc1 (derived from the CFB protein), with p values of 0.008 and 0.01, respectively, were elevated in NT1 samples compared with controls. In addition, the N-glycopeptide protein sources Ceruloplasmin, Complement factor B, and ITH4 were observed to play an important role in the complement activation and acute-phase response signaling pathways. This may explain the possible association between the biomarkers and pathophysiological effects.
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Affiliation(s)
- Mojgan Atashi
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA; (M.A.); (C.D.G.R.); (V.S.); (W.P.); (P.A.); (M.A.H.)
| | - Cristian D. Gutierrez Reyes
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA; (M.A.); (C.D.G.R.); (V.S.); (W.P.); (P.A.); (M.A.H.)
| | - Vishal Sandilya
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA; (M.A.); (C.D.G.R.); (V.S.); (W.P.); (P.A.); (M.A.H.)
| | - Waziha Purba
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA; (M.A.); (C.D.G.R.); (V.S.); (W.P.); (P.A.); (M.A.H.)
| | - Parisa Ahmadi
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA; (M.A.); (C.D.G.R.); (V.S.); (W.P.); (P.A.); (M.A.H.)
| | - Md. Abdul Hakim
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA; (M.A.); (C.D.G.R.); (V.S.); (W.P.); (P.A.); (M.A.H.)
| | - Firas Kobeissy
- Department of biochemistry and molecular genetics, Faculty of Biochemistry and Molecular Genetics, American University of Beirut, Beirut 11072020, Lebanon;
- Department of Neurobiology, Center for Neurotrauma, Multiomics & Biomarkers (CNMB), Neuroscience Institute, Morehouse School of Medicine, Atlanta, GE 30310, USA
| | - Giuseppe Plazzi
- IRCCS, Instituto delle Scienze Neurologiche di Bologna, 40124 Bologna, Italy; (G.P.); (M.M.)
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Monica Moresco
- IRCCS, Instituto delle Scienze Neurologiche di Bologna, 40124 Bologna, Italy; (G.P.); (M.M.)
| | - Bartolo Lanuzza
- Sleep Research Center, Department of Neurology IC, Oasi Research Institute-IRCCS, 94018 Tronia, Italy; (B.L.); (R.F.)
| | - Raffaele Ferri
- Sleep Research Center, Department of Neurology IC, Oasi Research Institute-IRCCS, 94018 Tronia, Italy; (B.L.); (R.F.)
| | - Yehia Mechref
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA; (M.A.); (C.D.G.R.); (V.S.); (W.P.); (P.A.); (M.A.H.)
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10
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Cichocki F, Zhang B, Wu CY, Chiu E, Day A, O’Connor RS, Yackoubov D, Simantov R, McKenna DH, Cao Q, Defor TE, Janakiram M, Wangen R, Cayci Z, Snyder N, Kumar A, Grzywacz B, Hwang J, Geffen Y, Miller JS, Maakaron J, Bachanova V. Nicotinamide enhances natural killer cell function and yields remissions in patients with non-Hodgkin lymphoma. Sci Transl Med 2023; 15:eade3341. [PMID: 37467318 PMCID: PMC10859734 DOI: 10.1126/scitranslmed.ade3341] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 06/29/2023] [Indexed: 07/21/2023]
Abstract
Allogeneic natural killer (NK) cell adoptive transfer has shown the potential to induce remissions in relapsed or refractory leukemias and lymphomas, but strategies to enhance NK cell survival and function are needed to improve clinical efficacy. Here, we demonstrated that NK cells cultured ex vivo with interleukin-15 (IL-15) and nicotinamide (NAM) exhibited stable induction of l-selectin (CD62L), a lymphocyte adhesion molecule important for lymph node homing. High frequencies of CD62L were associated with elevated transcription factor forkhead box O1 (FOXO1), and NAM promoted the stability of FOXO1 by preventing proteasomal degradation. NK cells cultured with NAM exhibited metabolic changes associated with elevated glucose flux and protection against oxidative stress. NK cells incubated with NAM also displayed enhanced cytotoxicity and inflammatory cytokine production and preferentially persisted in xenogeneic adoptive transfer experiments. We also conducted a first-in-human phase 1 clinical trial testing adoptive transfer of NK cells expanded ex vivo with IL-15 and NAM (GDA-201) combined with monoclonal antibodies in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) (NCT03019666). Cellular therapy with GDA-201 and rituximab was well tolerated and yielded an overall response rate of 74% in 19 patients with advanced NHL. Thirteen patients had a complete response, and 1 patient had a partial response. GDA-201 cells were detected for up to 14 days in blood, bone marrow, and tumor tissues and maintained a favorable metabolic profile. The safety and efficacy of GDA-201 in this study support further development as a cancer therapy.
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Affiliation(s)
- Frank Cichocki
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
| | - Bin Zhang
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
| | - Cheng-Ying Wu
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
| | - Emily Chiu
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
| | - Abderrahman Day
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
- University of Minnesota Institute for Health Informatics, University of Minnesota, Minneapolis, MN 55455, USA
| | - Roddy S. O’Connor
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | | | | | - David H. McKenna
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Qing Cao
- Biostatistics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Todd E. Defor
- Biostatistics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Murali Janakiram
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
| | - Rose Wangen
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
| | - Zuzan Cayci
- Division of Radiology, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
| | - Nathaniel Snyder
- Metabolic Disease Research and Thrombosis Research Center, Departments of Cardiovascular Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19104, USA
| | - Akhilesh Kumar
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
| | - Bartosz Grzywacz
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Justin Hwang
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
| | | | - Jeffrey S. Miller
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
| | - Joseph Maakaron
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
| | - Veronika Bachanova
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
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11
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Pinto D, Parameswaran R. Role of Truncated O-GalNAc Glycans in Cancer Progression and Metastasis in Endocrine Cancers. Cancers (Basel) 2023; 15:3266. [PMID: 37444377 DOI: 10.3390/cancers15133266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/16/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023] Open
Abstract
Glycans are an essential part of cells, playing a fundamental role in many pathophysiological processes such as cell differentiation, adhesion, motility, signal transduction, host-pathogen interactions, tumour cell invasion, and metastasis development. These glycans are also able to exert control over the changes in tumour immunogenicity, interfering with tumour-editing events and leading to immune-resistant cancer cells. The incomplete synthesis of O-glycans or the formation of truncated glycans such as the Tn-antigen (Thomsen nouveau; GalNAcα- Ser/Thr), its sialylated version the STn-antigen (sialyl-Tn; Neu5Acα2-6GalNAcα-Ser/Thr) and the elongated T-antigen (Thomsen-Friedenreich; Galβ1-3GalNAcα-Ser/Thr) has been shown to be associated with tumour progression and metastatic state in many human cancers. Prognosis in various human cancers is significantly poor when they dedifferentiate or metastasise. Recent studies in glycobiology have shown truncated O-glycans to be a hallmark of cancer cells, and when expressed, increase the oncogenicity by promoting dedifferentiation, risk of metastasis by impaired adhesion (mediated by selectins and integrins), and resistance to immunological killing by NK cells. Insight into these truncated glycans provides a complimentary and attractive route for cancer antigen discovery. The recent emergence of immunotherapies against cancers is predicted to harness the potential of using such agents against cancer-associated truncated glycans. In this review, we explore the role of truncated O-glycans in cancer progression and metastasis along with some recent studies on the role of O-glycans in endocrine cancers affecting the thyroid and adrenal gland.
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Affiliation(s)
- Diluka Pinto
- Division of Endocrine Surgery, National University Hospital, Singapore 119074, Singapore
| | - Rajeev Parameswaran
- Division of Endocrine Surgery, National University Hospital, Singapore 119074, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
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12
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Peng W, Reyes CDG, Gautam S, Yu A, Cho BG, Goli M, Donohoo K, Mondello S, Kobeissy F, Mechref Y. MS-based glycomics and glycoproteomics methods enabling isomeric characterization. MASS SPECTROMETRY REVIEWS 2023; 42:577-616. [PMID: 34159615 PMCID: PMC8692493 DOI: 10.1002/mas.21713] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/01/2021] [Accepted: 06/02/2021] [Indexed: 05/03/2023]
Abstract
Glycosylation is one of the most significant and abundant posttranslational modifications in mammalian cells. It mediates a wide range of biofunctions, including cell adhesion, cell communication, immune cell trafficking, and protein stability. Also, aberrant glycosylation has been associated with various diseases such as diabetes, Alzheimer's disease, inflammation, immune deficiencies, congenital disorders, and cancers. The alterations in the distributions of glycan and glycopeptide isomers are involved in the development and progression of several human diseases. However, the microheterogeneity of glycosylation brings a great challenge to glycomic and glycoproteomic analysis, including the characterization of isomers. Over several decades, different methods and approaches have been developed to facilitate the characterization of glycan and glycopeptide isomers. Mass spectrometry (MS) has been a powerful tool utilized for glycomic and glycoproteomic isomeric analysis due to its high sensitivity and rich structural information using different fragmentation techniques. However, a comprehensive characterization of glycan and glycopeptide isomers remains a challenge when utilizing MS alone. Therefore, various separation methods, including liquid chromatography, capillary electrophoresis, and ion mobility, were developed to resolve glycan and glycopeptide isomers before MS. These separation techniques were coupled to MS for a better identification and quantitation of glycan and glycopeptide isomers. Additionally, bioinformatic tools are essential for the automated processing of glycan and glycopeptide isomeric data to facilitate isomeric studies in biological cohorts. Here in this review, we discuss commonly employed MS-based techniques, separation hyphenated MS methods, and software, facilitating the separation, identification, and quantitation of glycan and glycopeptide isomers.
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Affiliation(s)
- Wenjing Peng
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, USA
| | | | - Sakshi Gautam
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, USA
| | - Aiying Yu
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, USA
| | - Byeong Gwan Cho
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, USA
| | - Mona Goli
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, USA
| | - Kaitlyn Donohoo
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, USA
| | | | - Firas Kobeissy
- Program for Neurotrauma, Neuroproteomics & Biomarkers Research, Departments of Emergency Medicine, University of Florida, Gainesville, Florida, USA
| | - Yehia Mechref
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, USA
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13
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Matsubara T. Peptide mimotopes to emulate carbohydrates. Chem Soc Rev 2022; 51:8160-8173. [PMID: 36128765 DOI: 10.1039/d2cs00470d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Glycoconjugates on animal cell surfaces are involved in numerous biological functions and diseases, especially the adhesion/metastasis of cancer cells, infection, and the onset of glycan-related diseases. In addition to glycoantigen detection, the regulation of glycan (carbohydrate)-protein interactions is needed to develop therapeutic strategies for glycan-related diseases. Preparation of a diverse range of glycan derivatives requires a massive effort, but the preparation and identification of alternative glycan-mimetic peptide mimotopes may provide a solution to this issue. Peptide mimotopes are recognized by glycan-binding proteins, such as lectins, enzymes, and antibodies, alternative to glycan ligands. Phage-display technology is the first choice in the selection of "glycan (carbohydrate)-mimetic peptide mimotopes" from a large repertoire of library sequences. This tutorial review describes the advantages of peptide mimotopes in comparison to glycan ligands, as well as their structural and functional mimicry. The detailed library design is followed by a description of the strategy used to improve affinity, and finally, an outline of the vaccine application of glycan-mimetic peptides is provided.
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Affiliation(s)
- Teruhiko Matsubara
- Department of Biosciences and Informatics, Keio University, 3-14-1 Hiyoshi, Kouhoku-ku, Yokohama 223-8522, Japan.
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14
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Inokuchi JI, Hosono M. Fond Memories of Professor Sen-itiroh Hakomori. J Biochem 2022; 172:143-145. [PMID: 36065662 DOI: 10.1093/jb/mvac039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 03/15/2022] [Indexed: 11/13/2022] Open
Affiliation(s)
- Jin-Ichi Inokuchi
- Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology (IMBG), Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi, 981-8558, Japan.,Forefront Research Center, Graduate School of Sciences, Osaka University, Machikaneyama, Toyonaka, Osaka 560-0043, Japan
| | - Masahiro Hosono
- Division of Cell Recognition, Institute of Molecular Biomembrane and Glycobiology (IMBG), Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi, 981-8558, Japan
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15
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Blood group antigens SLeX, SLeA, and LeY as prognostic markers in endometrial cancer. J Cancer Res Clin Oncol 2022; 148:3323-3335. [PMID: 35729354 DOI: 10.1007/s00432-022-04098-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 05/27/2022] [Indexed: 12/24/2022]
Abstract
PURPOSE Endometrial cancer (EC) is the most common gynecological cancer worldwide. Treatment has been improved in recent years, but, in advanced stages, therapeutical options are still limited. It has been reported that the expression of the blood group antigens Sialyl Lewis X (SLeX), Sialyl Lewis A (SLeA) and Lewis Y (LeY) is associated with prognosis in several tumors. Large studies on endometrial and cervical cancer are still pending. METHODS Specimens of 234 patients with EC were immunohistochemically stained with antibodies for SLeX, SLeA and LeY. Expression was correlated to histopathological variables. RESULTS High expression of SLeX was correlated to low pT-stage (p = 0.013), low grade (p < 0.001), low FIGO-stage (p = 0.006) and better overall survival rates (OS; p = 0.023). High expression of SLeA was associated with low pT-stage (p = 0.013), low grade (p = 0.001) and better progression-free survival (PFS; p = 0.043). LeY staining was correlated to pN + (p = 0.038), low grade (p = 0.005) and poorer PFS (p = 0.022). CONCLUSION This is the first study examining the expression of SLeX, SLeA and LeY in EC, which can serve as additional future prognostic markers. Further studies are necessary to understand the underlying mechanisms. The study was approved by the local ethics committee of the Ludwig-Maximilians University Munich (reference number 19-249).
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16
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Lumibao JC, Tremblay JR, Hsu J, Engle DD. Altered glycosylation in pancreatic cancer and beyond. J Exp Med 2022; 219:e20211505. [PMID: 35522218 PMCID: PMC9086500 DOI: 10.1084/jem.20211505] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 03/29/2022] [Accepted: 04/11/2022] [Indexed: 12/20/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest cancers and is projected to soon be the second leading cause of cancer death. Median survival of PDA patients is 6-10 mo, with the majority of diagnoses occurring at later, metastatic stages that are refractory to treatment and accompanied by worsening prognoses. Glycosylation is one of the most common types of post-translational modifications. The complex landscape of glycosylation produces an extensive repertoire of glycan moieties, glycoproteins, and glycolipids, thus adding a dynamic and tunable level of intra- and intercellular signaling regulation. Aberrant glycosylation is a feature of cancer progression and influences a broad range of signaling pathways to promote disease onset and progression. However, despite being so common, the functional consequences of altered glycosylation and their potential as therapeutic targets remain poorly understood and vastly understudied in the context of PDA. In this review, the functionality of glycans as they contribute to hallmarks of PDA are highlighted as active regulators of disease onset, tumor progression, metastatic capability, therapeutic resistance, and remodeling of the tumor immune microenvironment. A deeper understanding of the functional consequences of altered glycosylation will facilitate future hypothesis-driven studies and identify novel therapeutic strategies in PDA.
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Affiliation(s)
| | | | - Jasper Hsu
- Salk Institute for Biological Studies, La Jolla, CA
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17
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The role of the cell surface glycocalyx in drug delivery to and through the endothelium. Adv Drug Deliv Rev 2022; 184:114195. [PMID: 35292326 DOI: 10.1016/j.addr.2022.114195] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/05/2022] [Accepted: 03/08/2022] [Indexed: 11/20/2022]
Abstract
Cell membranes are key interfaces where materials engineering meets biology. Traditionally regarded as just the location of receptors regulating the uptake of molecules, we now know that all mammalian cell membranes are 'sugar coated'. These sugars, or glycans, form a matrix bound at the cell membrane via proteins and lipids, referred to as the glycocalyx, which modulate access to cell membrane receptors crucial for interactions with drug delivery systems (DDS). Focusing on the key blood-tissue barrier faced by most DDS to enable transport from the place of administration to target sites via the circulation, we critically assess the design of carriers for interactions at the endothelial cell surface. We also discuss the current challenges for this area and provide opportunities for future research efforts to more fully engineer DDS for controlled, efficient, and targeted interactions with the endothelium for therapeutic application.
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18
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Murahashi M, Kogami A, Muramoto A, Hoshino H, Akama TO, Mitoma J, Goi T, Hirayama A, Okamura T, Nagaya T, Kobayashi M. Vascular E-selectin Expression Detected in Formalin-fixed, Paraffin-embedded Sections With an E-selectin Monoclonal Antibody Correlates With Ulcerative Colitis Activity. J Histochem Cytochem 2022; 70:299-310. [PMID: 35253509 PMCID: PMC8971687 DOI: 10.1369/00221554221085336] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
It is widely accepted that E-selectin, an inducible endothelial cell adhesion molecule, plays a critical role in the initial step of neutrophil recruitment to sites of acute inflammation. However, immunohistological analysis of E-selectin has been hampered by lack of E-selectin-specific monoclonal antibodies that can stain formalin-fixed, paraffin-embedded (FFPE) tissue sections. Here, we employed E-selectin•IgM (a soluble form of E-selectin) as immunogen, and then, after negative selection with L-selectin•IgM and P-selectin•IgM and screening of FFPE sections of both COS-1 cells overexpressing E-selectin and acute appendicitis tissues, we successfully generated an E-selectin-specific monoclonal antibody capable of staining FFPE tissue sections. We used this antibody, designated U12-12, to perform quantitative immunohistological analysis of 390 colonic mucosal biopsy specimens representing ulcerative colitis. We found that the higher the histological disease activity, the greater the number of vessels expressing E-selectin, an observation consistent with previous analyses of frozen tissue sections. Furthermore, in active ulcerative colitis, E-selectin-expressing vessels contained neutrophils attached to endothelial cells, presumably in the process of extravasation, which eventually could cause epithelial damage. These results overall indicate that U12-12 is effective for E-selectin immunohistochemistry in archived FFPE samples representing various human diseases.
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Affiliation(s)
| | | | | | | | - Tomoya O Akama
- Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan; Department of Pharmacology, Kansai Medical University, Hirakata, Japan
| | - Junya Mitoma
- Department of Medical Life Sciences, School of Medical Life Sciences, Kyushu University of Health and Welfare, Nobeoka, Japan
| | | | - Atsuhiro Hirayama
- Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takuma Okamura
- Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tadanobu Nagaya
- Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
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19
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Experimental and computational characterization of dynamic biomolecular interaction systems involving glycolipid glycans. Glycoconj J 2022; 39:219-228. [PMID: 35298725 DOI: 10.1007/s10719-022-10056-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/31/2022] [Accepted: 03/09/2022] [Indexed: 02/03/2023]
Abstract
On cell surfaces, carbohydrate chains that modify proteins and lipids mediate various biological functions, which are exerted not only through carbohydrate-protein interactions but also through carbohydrate-carbohydrate interactions. These glycans exhibit considerable degrees of conformational variability and often form clusters providing multiple binding sites. The integration of nuclear magnetic resonance spectroscopy and molecular dynamics simulation has made it possible to delineate the dynamical structures of carbohydrate chains. This approach has facilitated the remodeling of oligosaccharide conformational space in the prebound state to improve protein-binding affinity and has been applied to visualize dynamic carbohydrate-carbohydrate interactions that control glycoprotein-glycoprotein complex formation. Functional glycoclusters have been characterized by experimental and computational approaches applied to various model membranes and artificial self-assembling systems. This line of investigation has provided dynamic views of molecular assembling on glycoclusters, giving mechanistic insights into physiological and pathological molecular events on cell surfaces as well as clues for the design and creation of molecular systems exerting improved glycofunctions. Further development and accumulation of such studies will allow detailed understanding and artificial control of the "glycosynapse" foreseen by Dr. Sen-itiroh Hakomori.
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20
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Huang Y, Harris BS, Minami SA, Jung S, Shah PS, Nandi S, McDonald KA, Faller R. SARS-CoV-2 spike binding to ACE2 is stronger and longer ranged due to glycan interaction. Biophys J 2021; 121:79-90. [PMID: 34883069 PMCID: PMC8648368 DOI: 10.1016/j.bpj.2021.12.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 11/08/2021] [Accepted: 12/02/2021] [Indexed: 01/01/2023] Open
Abstract
Highly detailed steered molecular dynamics simulations are performed on differently glycosylated receptor binding domains of the severe acute respiratory syndrome coronavirus-2 spike protein. The binding strength and the binding range increase with glycosylation. The interaction energy rises very quickly when pulling the proteins apart and only slowly drops at larger distances. We see a catch-slip-type behavior whereby interactions during pulling break and are taken over by new interactions forming. The dominant interaction mode is hydrogen bonds, but Lennard-Jones and electrostatic interactions are relevant as well.
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Affiliation(s)
- Yihan Huang
- Department of Materials Science, UC Davis, Davis, California
| | | | - Shiaki A Minami
- Department of Chemical Engineering, UC Davis, Davis, California
| | - Seongwon Jung
- Department of Chemical Engineering, UC Davis, Davis, California
| | - Priya S Shah
- Department of Chemical Engineering, UC Davis, Davis, California; Department of Microbiology and Molecular Genetics, UC Davis, Davis, California
| | - Somen Nandi
- Department of Chemical Engineering, UC Davis, Davis, California; Global HealthShare Initiative, UC Davis, Davis, California
| | - Karen A McDonald
- Department of Chemical Engineering, UC Davis, Davis, California; Global HealthShare Initiative, UC Davis, Davis, California
| | - Roland Faller
- Department of Chemical Engineering, UC Davis, Davis, California.
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21
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Nudelman E. Sen-itiroh Hakomori and tumor-associated glycosphingolipids: an astoundingly productive decade, 1980-1990. Glycoconj J 2021; 38:709-715. [PMID: 34826038 DOI: 10.1007/s10719-021-10026-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 10/04/2021] [Indexed: 10/19/2022]
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22
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Singh Aidhen I, Thoti N. Natural Products & Bioactivity Inspired Synthetic Pursuits Interfacing with Carbohydrates: Ongoing Journey with C-Glycosides. CHEM REC 2021; 21:3131-3177. [PMID: 34714570 DOI: 10.1002/tcr.202100216] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 09/27/2021] [Indexed: 12/14/2022]
Abstract
Natural products, remains the most important source for the discovery of new drugs for the treatment of human diseases. This has inspired the synthetic community to design and develop mimics of natural products either to answer important questions in biology or to explore their therapeutic potentials. Glycosides present themselves abundantly in nature, right from the cell surface receptors to natural products of any origin. The O-Glycosides are hydrolytically less stable compared to C-glycosides and this feature has presented a great opportunity for drug discovery. The discovery of Dapagliflozin, an SGLT inhibitor and C-glucoside, for the treatment of diabetes is one such example. Aryl acyl-anion chemistry has been explored for the synthesis of 2-deoxy-C-aryl furanoside/pyranoside/septanosides. Besides success, the studies have provided valuable insight into the natural propensities of the architectural framework for the cascade to furan derivatives. The aryl acyl-anion chemistry has also enabled the synthesis of biologically active diaryl heptanoids. Inspired from sucesss of Dapagliflozin, new analogues have been synthesized with pyridine and isocoumarin heterocycle as the proximal ring. C-glucosides of isoliquiritigenin have been synthesized for the first time and evaluated as an efficient aldose reductase inhibitor. The synthesis and evaluation of acyl-C-β-D-glucosides and benzyl-C-β-D-glucoside as glucose-uptake promoters has revealed promise in small molecules. The concept of building blocks has been used to obtain natural oxylipins, D-xylo and L-xylo-configured alkane tetrols and novel lipophilic ketones with erythro/threo configured trihydroxy polar head-group as possible anti-mycobacterial agents.
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Affiliation(s)
- Indrapal Singh Aidhen
- Department of Chemistry, Indian Institute of Technology Madras, Chennai, 600036, India
| | - Naveenkumar Thoti
- Department of Chemistry, Indian Institute of Technology Madras, Chennai, 600036, India
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23
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Unique Tropism and Entry Mechanism of Mumps Virus. Viruses 2021; 13:v13091746. [PMID: 34578327 PMCID: PMC8471308 DOI: 10.3390/v13091746] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 08/28/2021] [Accepted: 08/30/2021] [Indexed: 12/19/2022] Open
Abstract
Mumps virus (MuV) is an important human pathogen that causes parotitis, orchitis, oophoritis, meningitis, encephalitis, and sensorineural hearing loss. Although mumps is a vaccine-preventable disease, sporadic outbreaks have occurred worldwide, even in highly vaccinated populations. MuV not only causes systemic infection but also has a unique tropism to glandular tissues and the central nervous system. In general, tropism can be defined by multiple factors in the viral life cycle, including its entry, interaction with host factors, and host-cell immune responses. Although the underlying mechanisms of MuV tropism remain to be fully understood, recent studies on virus-host interactions have provided insights into viral pathogenesis. This review was aimed at summarizing the entry process of MuV by focusing on the glycan receptors, particularly the recently identified receptors with a trisaccharide core motif, and their interactions with the viral attachment proteins. Here, we describe the receptor structures, their distribution in the human body, and the recently identified host factors for MuV and analyze their relationship with MuV tropism.
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Foda AAM, Alamer HA, Ikram N, Helali HA, Fayad FS, Hussian SW, Abdelwahab K, Akl T, Emarah Z, Ramez AM. Expression of CD10 and CD15 in colorectal mucinous and signet ring adenocarcinomas and its relation to clinicopathological features and prognosis. Cancer Biomark 2021; 33:143-150. [PMID: 34487022 DOI: 10.3233/cbm-210067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND CD10 and CD15 expression has been reported in several tumors. Whether CD10 and CD15 have a role in colorectal mucinous and signet ring adenocarcinoma (MSA) tumorigenesis is not yet known. OBJECTIVE We aimed to investigate the role of CD10 and CD15 expression in mucinous colorectal adenoma-carcinoma sequence (ACS) and determine if there is any clinical and prognostic significance associated with their expression. METHODS Seventy-five cases of colorectal MSA, and 9 cases of adenoma samples were collected. Manual TMA blocks were constructed and immunohistochemistry for CD10 and CD15 was done. RESULTS Compared to adenomas, CD15 expression was significantly higher in MSA (p= 0.002), in contrast to CD10 expression. CD15 positivity was significantly associated with microsatellite stable (MSS) tumors (p= 0.018). The association between CD10 positivity and fungating tumor growth showed marginal significance. Unlike CD10, CD15 positivity showed significant association with overall survival of colorectal MSA patients. CONCLUSIONS CD15 expression seems to have a role in mucinous colorectal ACS, with significant impact on the survival of MSA patients. Further studies are suggested to identify any genetic alterations that may underlie a potential association with disease progression.
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Affiliation(s)
- Abd AlRahman Mohammad Foda
- Department of Pathology, Mansoura University, Mansoura, Egypt.,Batterjee Medical College for Sciences and Technology, Jeddah, Saudi Arabia
| | | | - Nadeem Ikram
- Batterjee Medical College for Sciences and Technology, Jeddah, Saudi Arabia
| | | | - Fayza Sami Fayad
- Batterjee Medical College for Sciences and Technology, Jeddah, Saudi Arabia
| | | | | | - Tamer Akl
- Department of Medical Oncology, Mansoura University, Mansoura, Egypt
| | - Ziad Emarah
- Department of Medical Oncology, Mansoura University, Mansoura, Egypt
| | - Ahmed M Ramez
- Department of Medical Oncology, Mansoura University, Mansoura, Egypt
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25
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Smith BAH, Bertozzi CR. The clinical impact of glycobiology: targeting selectins, Siglecs and mammalian glycans. Nat Rev Drug Discov 2021; 20:217-243. [PMID: 33462432 PMCID: PMC7812346 DOI: 10.1038/s41573-020-00093-1] [Citation(s) in RCA: 280] [Impact Index Per Article: 70.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/29/2020] [Indexed: 01/31/2023]
Abstract
Carbohydrates - namely glycans - decorate every cell in the human body and most secreted proteins. Advances in genomics, glycoproteomics and tools from chemical biology have made glycobiology more tractable and understandable. Dysregulated glycosylation plays a major role in disease processes from immune evasion to cognition, sparking research that aims to target glycans for therapeutic benefit. The field is now poised for a boom in drug development. As a harbinger of this activity, glycobiology has already produced several drugs that have improved human health or are currently being translated to the clinic. Focusing on three areas - selectins, Siglecs and glycan-targeted antibodies - this Review aims to tell the stories behind therapies inspired by glycans and to outline how the lessons learned from these approaches are paving the way for future glycobiology-focused therapeutics.
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Affiliation(s)
- Benjamin A H Smith
- Department of Chemical & Systems Biology and ChEM-H, Stanford School of Medicine, Stanford, CA, USA
| | - Carolyn R Bertozzi
- Department of Chemical & Systems Biology and ChEM-H, Stanford School of Medicine, Stanford, CA, USA.
- Department of Chemistry, Stanford University, Stanford, CA, USA.
- Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
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26
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Hong S, Yu C, Wang P, Shi Y, Cao W, Cheng B, Chapla DG, Ma Y, Li J, Rodrigues E, Narimatsu Y, Yates JR, Chen X, Clausen H, Moremen KW, Macauley MS, Paulson JC, Wu P. Glycoengineering of NK Cells with Glycan Ligands of CD22 and Selectins for B‐Cell Lymphoma Therapy. Angew Chem Int Ed Engl 2021. [DOI: 10.1002/ange.202005934] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Senlian Hong
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA 92037 USA
| | - Chenhua Yu
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA 92037 USA
- Tianjin Medical University Cancer Institute & Hospital Key laboratory of Breast Cancer Prevention and Therapy School of Medicine Nankai University Tianjin 300071 China
| | - Peng Wang
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA 92037 USA
| | - Yujie Shi
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA 92037 USA
| | - Weiqian Cao
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA 92037 USA
- Department of Chemistry and Institutes of Biomedical Sciences The Fifth People's Hospital Fudan University Shanghai 200433 China
| | - Bo Cheng
- College of Chemistry and Molecular Engineering Beijing University Beijing 100871 China
| | | | - Yuanhui Ma
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA 92037 USA
| | - Jie Li
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA 92037 USA
| | - Emily Rodrigues
- Department of Chemistry University of Alberta 11227 Saskatchewan Dr NW Edmonton, AB T6G 2G2 Alberta Canada
| | - Yoshiki Narimatsu
- Copenhagen Center for Glycomics Department of Cellular and Molecular Medicine University of Copenhagen Copenhagen Denmark
| | - John R. Yates
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA 92037 USA
| | - Xing Chen
- College of Chemistry and Molecular Engineering Beijing University Beijing 100871 China
| | - Henrik Clausen
- Copenhagen Center for Glycomics Department of Cellular and Molecular Medicine University of Copenhagen Copenhagen Denmark
| | - Kelly W. Moremen
- Complex Carbohydrate Research Center University of Georgia Athens GA 30602 USA
| | - Matthew Scott Macauley
- Department of Chemistry University of Alberta 11227 Saskatchewan Dr NW Edmonton, AB T6G 2G2 Alberta Canada
| | - James C. Paulson
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA 92037 USA
| | - Peng Wu
- Department of Molecular Medicine The Scripps Research Institute La Jolla CA 92037 USA
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27
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Hong S, Yu C, Wang P, Shi Y, Cao W, Cheng B, Chapla DG, Ma Y, Li J, Rodrigues E, Narimatsu Y, Yates JR, Chen X, Clausen H, Moremen KW, Macauley MS, Paulson JC, Wu P. Glycoengineering of NK Cells with Glycan Ligands of CD22 and Selectins for B-Cell Lymphoma Therapy. Angew Chem Int Ed Engl 2021; 60:3603-3610. [PMID: 33314603 PMCID: PMC7980786 DOI: 10.1002/anie.202005934] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/14/2020] [Indexed: 12/29/2022]
Abstract
CD22, a member of Siglec family of sialic acid binding proteins, has restricted expression on B cells. Antibody-based agents targeting CD22 or CD20 on B lymphoma and leukemia cells exhibit clinical efficacy for treating these malignancies, but also attack normal B cells leading to immune deficiency. Here, we report a chemoenzymatic glycocalyx editing strategy to introduce high-affinity and specific CD22 ligands onto NK-92MI and cytokine-induced natural killer cells to achieve tumor-specific CD22 targeting. These CD22-ligand modified cells exhibited significantly enhanced tumor cell binding and killing in vitro without harming healthy B cells. For effective lymphoma cell killing in vivo, we further functionalized CD22 ligand-modified NK-92MI cells with the E-selectin ligand sialyl Lewis X to promote trafficking to bone marrow. The dual-functionalized cells resulted in the efficient suppression of B lymphoma in a xenograft model. Our results suggest that natural killer cells modified with glycan ligands to CD22 and selectins promote both targeted killing of B lymphoma cells and improved trafficking to sites where the cancer cells reside, respectively.
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Affiliation(s)
- Senlian Hong
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Chenhua Yu
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
- Tianjin Medical University Cancer Institute & Hospital, Key laboratory of Breast Cancer Prevention and Therapy, School of Medicine, Nankai University, Tianjin, 300071, China
| | - Peng Wang
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Yujie Shi
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Weiqian Cao
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
- Department of Chemistry and Institutes of Biomedical Sciences, The Fifth People's Hospital, Fudan University, Shanghai, 200433, China
| | - Bo Cheng
- College of Chemistry and Molecular Engineering, Beijing University, Beijing, 100871, China
| | - Digantkumar G Chapla
- Complex Carbohydrate Research Center, University of Georgia, Athens, GA, 30602, USA
| | - Yuanhui Ma
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Jie Li
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Emily Rodrigues
- Department of Chemistry, University of Alberta, 11227 Saskatchewan Dr NW, Edmonton, AB, T6G 2G2, Alberta, Canada
| | - Yoshiki Narimatsu
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - John R Yates
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Xing Chen
- College of Chemistry and Molecular Engineering, Beijing University, Beijing, 100871, China
| | - Henrik Clausen
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Kelly W Moremen
- Complex Carbohydrate Research Center, University of Georgia, Athens, GA, 30602, USA
| | - Matthew Scott Macauley
- Department of Chemistry, University of Alberta, 11227 Saskatchewan Dr NW, Edmonton, AB, T6G 2G2, Alberta, Canada
| | - James C Paulson
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Peng Wu
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
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Laine RA, Gahmberg CC, Sekiguchi K, Kannagi R, Nudelman ED, Clausen H. Professor Sen-itiroh Hakomori (1929-2020) A tribute to a remarkable glycobiologist, mentor, and friend! Glycobiology 2021; 31:708-712. [PMID: 33527981 DOI: 10.1093/glycob/cwab006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 01/18/2021] [Indexed: 11/14/2022] Open
Affiliation(s)
- Roger A Laine
- Depts of Biological Sciences and Chemistry, Louisiana State University, Baton Rouge, LA 70808
| | - Carl C Gahmberg
- Programme in Molecular and Systemic Biosciences, University of Helsinki, Viikinkaari 9, 00014 Helsinki, Finland
| | - Kiyotoshi Sekiguchi
- Institute for Protein Research, Osaka University, 3-2 Yamadaoka Suita, Osaka 565-0871, Japan
| | - Reiji Kannagi
- Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan
| | | | - Henrik Clausen
- Copenhagen Centre for Glycomics, University of Copenhagen, Department of Cellular and Molecular Medicine, Nørre Alle 14, DK-2200 Copenhagen N, Denmark
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29
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Hatzade KM, Ghatole AM, Gaidhane PK, Gaidhane MK, Gadekar GP. A facile synthesis of some new pyrimidine-2,4,6-triones analogs and their O-β-D-glucosides P-glycoprotein and antioxidant, antimicrobial study, blood–brain barrier, cytochrome p450 enzyme activity prediction. Med Chem Res 2020. [DOI: 10.1007/s00044-020-02649-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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30
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Amicucci MJ, Nandita E, Galermo AG, Castillo JJ, Chen S, Park D, Smilowitz JT, German JB, Mills DA, Lebrilla CB. A nonenzymatic method for cleaving polysaccharides to yield oligosaccharides for structural analysis. Nat Commun 2020; 11:3963. [PMID: 32770134 PMCID: PMC7414865 DOI: 10.1038/s41467-020-17778-1] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 07/15/2020] [Indexed: 12/22/2022] Open
Abstract
Polysaccharides are the most abundant biomolecules in nature, but are the least understood in terms of their chemical structures and biological functions. Polysaccharides cannot be simply sequenced because they are often highly branched and lack a uniform structure. Furthermore, large polymeric structures cannot be directly analyzed by mass spectrometry techniques, a problem that has been solved for polynucleotides and proteins. While restriction enzymes have advanced genomic analysis, and trypsin has advanced proteomic analysis, there has been no equivalent enzyme for universal polysaccharide digestion. We describe the development and application of a chemical method for producing oligosaccharides from polysaccharides. The released oligosaccharides are characterized by advanced liquid chromatography-mass spectrometry (LC-MS) methods with high sensitivity, accuracy and throughput. The technique is first used to identify polysaccharides by oligosaccharide fingerprinting. Next, the polysaccharide compositions of food and feces are determined, further illustrating the utility of technique in food and clinical studies.
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Affiliation(s)
- Matthew J Amicucci
- Agricultural and Environmental Chemistry Graduate Group, University of California, Davis, CA, USA
- Department of Chemistry, University of California, Davis, CA, USA
- Foods For Health Institute, University of California, Davis, CA, USA
| | - Eshani Nandita
- Department of Chemistry, University of California, Davis, CA, USA
- Foods For Health Institute, University of California, Davis, CA, USA
| | - Ace G Galermo
- Department of Chemistry, University of California, Davis, CA, USA
- Foods For Health Institute, University of California, Davis, CA, USA
| | - Juan Jose Castillo
- Department of Chemistry, University of California, Davis, CA, USA
- Foods For Health Institute, University of California, Davis, CA, USA
| | - Siyu Chen
- Department of Chemistry, University of California, Davis, CA, USA
- Foods For Health Institute, University of California, Davis, CA, USA
| | - Dayoung Park
- Department of Chemistry, University of California, Davis, CA, USA
- Foods For Health Institute, University of California, Davis, CA, USA
| | - Jennifer T Smilowitz
- Foods For Health Institute, University of California, Davis, CA, USA
- Department of Food Science and Technology, University of California, Davis, CA, USA
| | - J Bruce German
- Foods For Health Institute, University of California, Davis, CA, USA
- Department of Food Science and Technology, University of California, Davis, CA, USA
| | - David A Mills
- Foods For Health Institute, University of California, Davis, CA, USA
- Department of Food Science and Technology, University of California, Davis, CA, USA
| | - Carlito B Lebrilla
- Agricultural and Environmental Chemistry Graduate Group, University of California, Davis, CA, USA.
- Department of Chemistry, University of California, Davis, CA, USA.
- Foods For Health Institute, University of California, Davis, CA, USA.
- Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA.
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31
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Venkatakrishnan V, Dieckmann R, Loke I, Tjondro HC, Chatterjee S, Bylund J, Thaysen-Andersen M, Karlsson NG, Karlsson-Bengtsson A. Glycan analysis of human neutrophil granules implicates a maturation-dependent glycosylation machinery. J Biol Chem 2020; 295:12648-12660. [PMID: 32665399 DOI: 10.1074/jbc.ra120.014011] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 06/15/2020] [Indexed: 12/12/2022] Open
Abstract
Protein glycosylation is essential to trafficking and immune functions of human neutrophils. During granulopoiesis in the bone marrow, distinct neutrophil granules are successively formed. Distinct receptors and effector proteins, many of which are glycosylated, are targeted to each type of granule according to their time of expression, a process called "targeting by timing." Therefore, these granules are time capsules reflecting different times of maturation that can be used to understand the glycosylation process during granulopoiesis. Herein, neutrophil subcellular granules were fractionated by Percoll density gradient centrifugation, and N- and O-glycans present in each compartment were analyzed by LC-MS. We found abundant paucimannosidic N-glycans and lack of O-glycans in the early-formed azurophil granules, whereas the later-formed specific and gelatinase granules and secretory vesicles contained complex N- and O-glycans with remarkably elongated N-acetyllactosamine repeats with Lewis epitopes. Immunoblotting and histochemical analysis confirmed the expression of Lewis X and sialyl-Lewis X in the intracellular granules and on the cell surface, respectively. Many glycans identified are unique to neutrophils, and their complexity increased progressively from azurophil granules to specific granules and then to gelatinase granules, suggesting temporal changes in the glycosylation machinery indicative of "glycosylation by timing" during granulopoiesis. In summary, this comprehensive neutrophil granule glycome map, the first of its kind, highlights novel granule-specific glycosylation features and is a crucial first step toward a better understanding of the mechanisms regulating protein glycosylation during neutrophil granulopoiesis and a more detailed understanding of neutrophil biology and function.
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Affiliation(s)
- Vignesh Venkatakrishnan
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Régis Dieckmann
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ian Loke
- Department of Molecular Sciences, Macquarie University, Sydney, Australia.,Cordlife Group Limited, Singapore
| | - Harry C Tjondro
- Department of Molecular Sciences, Macquarie University, Sydney, Australia
| | | | - Johan Bylund
- Department of Oral Microbiology and Immunology, Institute of Odontology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Morten Thaysen-Andersen
- Department of Molecular Sciences, Macquarie University, Sydney, Australia.,Biomolecular Discovery Research Centre, Macquarie University, Sydney, Australia
| | - Niclas G Karlsson
- Department of Medical Chemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anna Karlsson-Bengtsson
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
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Abstract
Mucosal-associated invariant T (MAIT) cells have been attracting increasing attention over the last few years as a potent unconventional T cell subset. Three factors largely account for this emerging interest. Firstly, these cells are abundant in humans, both in circulation and especially in some tissues such as the liver. Secondly is the discovery of a ligand that has uncovered their microbial targets, and also allowed for the development of tools to accurately track the cells in both humans and mice. Finally, it appears that the cells not only have a diverse range of functions but also are sensitive to a range of inflammatory triggers that can enhance or even bypass T cell receptor–mediated signals—substantially broadening their likely impact in health and disease. In this review we discuss how MAIT cells display antimicrobial, homeostatic, and amplifier roles in vivo, and how this may lead to protection and potentially pathology.
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Affiliation(s)
- Nicholas M. Provine
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 9DU, United Kingdom
| | - Paul Klenerman
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 9DU, United Kingdom
- NIHR Biomedical Research Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom
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33
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Sagini MN, Klika KD, Hotz-Wagenblatt A, Zepp M, Berger MR. Lactosyl-sepharose binding proteins from pancreatic cancer cells show differential expression in primary and metastatic organs. Exp Biol Med (Maywood) 2020; 245:631-643. [PMID: 32131629 DOI: 10.1177/1535370220910691] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
In normal cells, glycan binding proteins mediate various cellular processes upon recognition and binding to respective ligands. In tumor cells, these proteins have been associated with metastasis. Lactosyl-sepharose binding proteins (LSBPs) were isolated and identified in a workflow involving lactosyl affinity chromatography and label-free quantification mass spectrometry (LFQ MS). A binding study with monosaccharides was performed by microscale thermophoresis and nuclear magnetic resonance spectroscopy. Influence of galactose on LSBPs’ binding to the lactosyl resin was investigated by competitive affinity chromatography followed by LFQ MS. An analysis of amino acids with sugar binding motifs was searched using bioinformatics tools. The expression profiles of these proteins at the mRNA level, as determined by a chip array from a pancreatic ductal adenocarcinoma (PDAC) liver metastasis model, were used for evaluating their potential role in cancer progression. Proteomics data and their respective genes were analyzed by MaxQuant and Ingenuity Pathway Analysis. In total, 1295 LSBPs were isolated and identified from Suit2-007 human pancreatic adenocarcinoma cells. Interaction studies revealed that these proteins exhibit low to moderate affinity for monosaccharide sugars. Some of these LSBPs even showed reduced affinity after calcium depletion. Among the isolated proteins were annexins and galectins in addition to other families, with no history of binding lactosyl residues. A subset of LSBPs exhibited differential profiles in the pancreas, liver, and lung environments. These modulations may be related to tumor progression. In conclusion, we show that PDAC cells contain LSBPs, a subset of which binds galactose with calcium dependency. The differential expression of these proteins in a rat model highlights their value for diagnosis and as potential drug targets for PDAC therapy. Future work will be required to validate these findings in patient samples.Impact statementInteraction of glycan binding proteins with aberrantly expressed glycans in tumor environment is crucial for metastasis. Here, we established a work flow for investigating the presence of a subset of these proteins in PDAC cells, which bind to a lactosyl-sepharose resin. The resin had been designed to isolate proteins with lectin-like properties. The corresponding lactosyl-sepharose binding proteins (LSBPs) show affinity for galactose and other monosaccharides. A subset of the LSBPs shows also calcium dependency. The importance of these proteins is highlighted by their differential expression profiles in PDAC cells growing in primary (pancreas) and metastatic (liver and lung) organ sites. Based on their affinity for the lactosyl-resin and monosaccharides, LSBPs hold potential for PDAC diagnosis and as drug targets. This work has set the stage for further investigation of the occurrence and the role of LSBPs in patient samples using the newly established workflow.
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Affiliation(s)
- Micah N Sagini
- Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Karel D Klika
- Molecular Structure Analysis, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Agnes Hotz-Wagenblatt
- Genomics and Proteomics Core Facility, Bioinformatics-Husar Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Michael Zepp
- Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Martin R Berger
- Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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34
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Abstract
Cell-cell interactions mediated by selectins and their ligand glycans play pivotal roles in a variety of biological processes represented by leukocyte recruitment to inflammatory sites, lymphocyte homing, and extravasation of cancer cells. The interactions are enhanced at least partly through the upregulation of the selectin-ligand glycan expression, which is observed, for instance, during the activation of leukocytes or epithelial-mesenchymal transition of cancer cells. Selectin-binding assays such as cell adhesion assay or rolling assay have long been used to directly evaluate the activity of these cells in the selectin-mediated processes. In this chapter, we introduce a highly quantitative assay by flow cytometry using recombinant selectin-Ig(Fc) chimera proteins, showing our procedure and tips for E-selectin-binding assay of colon cancer cells undergoing epithelial-mesenchymal transition.
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Affiliation(s)
- Keiichiro Sakuma
- Division of Pathophysiology, Aichi Cancer Center Research Institute, Nagoya, Japan.
| | - Reiji Kannagi
- The Institute of Biomedical Sciences (IBMS), Academia Sinica, Taipei, Taiwan
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35
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Regulation of cell adhesion: a collaborative effort of integrins, their ligands, cytoplasmic actors, and phosphorylation. Q Rev Biophys 2019; 52:e10. [PMID: 31709962 DOI: 10.1017/s0033583519000088] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Integrins are large heterodimeric type 1 membrane proteins expressed in all nucleated mammalian cells. Eighteen α-chains and eight β-chains can combine to form 24 different integrins. They are cell adhesion proteins, which bind to a large variety of cellular and extracellular ligands. Integrins are required for cell migration, hemostasis, translocation of cells out from the blood stream and further movement into tissues, but also for the immune response and tissue morphogenesis. Importantly, integrins are not usually active as such, but need activation to become adhesive. Integrins are activated by outside-in activation through integrin ligand binding, or by inside-out activation through intracellular signaling. An important question is how integrin activity is regulated, and this topic has recently drawn much attention. Changes in integrin affinity for ligand binding are due to allosteric structural alterations, but equally important are avidity changes due to integrin clustering in the plane of the plasma membrane. Recent studies have partially solved how integrin cell surface structures change during activation. The integrin cytoplasmic domains are relatively short, but by interacting with a variety of cytoplasmic proteins in a regulated manner, the integrins acquire a number of properties important not only for cell adhesion and movement, but also for cellular signaling. Recent work has shown that specific integrin phosphorylations play pivotal roles in the regulation of integrin activity. Our purpose in this review is to integrate the present knowledge to enable an understanding of how cell adhesion is dynamically regulated.
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36
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Microbial production of sialic acid and sialylated human milk oligosaccharides: Advances and perspectives. Biotechnol Adv 2019; 37:787-800. [DOI: 10.1016/j.biotechadv.2019.04.011] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 04/13/2019] [Accepted: 04/23/2019] [Indexed: 12/21/2022]
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Kubota M, Matsuoka R, Suzuki T, Yonekura K, Yanagi Y, Hashiguchi T. Molecular Mechanism of the Flexible Glycan Receptor Recognition by Mumps Virus. J Virol 2019; 93:e00344-19. [PMID: 31118251 PMCID: PMC6639266 DOI: 10.1128/jvi.00344-19] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 05/10/2019] [Indexed: 11/20/2022] Open
Abstract
Mumps virus (MuV) is an important aerosol-transmitted human pathogen causing epidemic parotitis, meningitis, encephalitis, and deafness. MuV preferentially uses a trisaccharide containing α2,3-linked sialic acid as a receptor. However, given the MuV tropism toward glandular tissues and the central nervous system, an additional glycan motif(s) may also serve as a receptor. Here, we performed a large-scale glycan array screen with MuV hemagglutinin-neuraminidase (MuV-HN) attachment proteins by using 600 types of glycans from The Consortium for Functional Glycomics Protein-Glycan Interaction Core in an effort to find new glycan receptor motif(s). According to the results of the glycan array, we successfully determined the crystal structures of MuV-HN proteins bound to newly identified glycan motifs, sialyl LewisX (SLeX) and the oligosaccharide portion of the GM2 ganglioside (GM2-glycan). Interestingly, the complex structures showed that SLeX and GM2-glycan share the same configuration with the reported trisaccharide motif, 3'-sialyllactose (3'-SL), at the binding site of MuV-HN, while SLeX and GM2-glycan have several unique interactions compared with those of 3'-SL. Thus, MuV-HN protein can allow an additional spatial modification in GM2-glycan and SLeX at the second and third carbohydrates from the nonreducing terminus of the core trisaccharide structure, respectively. Importantly, MuV entry was efficiently inhibited in the presence of 3'-SL, SLeX, or GM2-glycan derivatives, which indicates that these motifs can serve as MuV receptors. The α2,3-sialylated oligosaccharides, such as SLeX and 3'-sialyllactosamine, are broadly expressed in various tissues, and GM2 exists mainly in neural tissues and the adrenal gland. The distribution of these glycan motifs in human tissues/organs may have bearing on MuV tropism.IMPORTANCE Mumps virus (MuV) infection is characterized by parotid gland swelling and can cause pancreatitis, orchitis, meningitis, and encephalitis. MuV-related hearing loss is also a serious complication because it is usually irreversible. MuV outbreaks have been reported in many countries, even in high-vaccine-coverage areas. MuV has tropism toward glandular tissues and the central nervous system. To understand the unique MuV tropism, revealing the mechanism of receptor recognition by MuV is very important. Here, using a large-scale glycan array and X-ray crystallography, we show that MuV recognizes sialyl LewisX and GM2 ganglioside as receptors, in addition to a previously reported MuV receptor, a trisaccharide containing an α2,3-linked sialic acid. The flexible recognition of these glycan receptors by MuV may explain the unique tropism and pathogenesis of MuV. Structures will also provide a template for the development of effective entry inhibitors targeting the receptor-binding site of MuV.
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Affiliation(s)
- Marie Kubota
- Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka, Japan
| | - Rei Matsuoka
- RIKEN SPring-8 Center, Biostructural Mechanism Laboratory, Hyogo, Japan
| | - Tateki Suzuki
- Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka, Japan
| | - Koji Yonekura
- RIKEN SPring-8 Center, Biostructural Mechanism Laboratory, Hyogo, Japan
| | - Yusuke Yanagi
- Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka, Japan
| | - Takao Hashiguchi
- Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka, Japan
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Chandler KB, Costello CE, Rahimi N. Glycosylation in the Tumor Microenvironment: Implications for Tumor Angiogenesis and Metastasis. Cells 2019; 8:E544. [PMID: 31195728 PMCID: PMC6627046 DOI: 10.3390/cells8060544] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 05/31/2019] [Accepted: 06/01/2019] [Indexed: 01/27/2023] Open
Abstract
Just as oncogene activation and tumor suppressor loss are hallmarks of tumor development, emerging evidence indicates that tumor microenvironment-mediated changes in glycosylation play a crucial functional role in tumor progression and metastasis. Hypoxia and inflammatory events regulate protein glycosylation in tumor cells and associated stromal cells in the tumor microenvironment, which facilitates tumor progression and also modulates a patient's response to anti-cancer therapeutics. In this review, we highlight the impact of altered glycosylation on angiogenic signaling and endothelial cell adhesion, and the critical consequences of these changes in tumor behavior.
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Affiliation(s)
- Kevin Brown Chandler
- Center for Biomedical Mass Spectrometry, Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
| | - Catherine E Costello
- Center for Biomedical Mass Spectrometry, Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
| | - Nader Rahimi
- Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
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Li SS, Ip CKM, Tang MYH, Tang MKS, Tong Y, Zhang J, Hassan AA, Mak ASC, Yung S, Chan TM, Ip PP, Lee CL, Chiu PCN, Lee LTO, Lai HC, Zeng JZ, Shum HC, Wong AST. Sialyl Lewis x-P-selectin cascade mediates tumor-mesothelial adhesion in ascitic fluid shear flow. Nat Commun 2019; 10:2406. [PMID: 31160622 PMCID: PMC6547673 DOI: 10.1038/s41467-019-10334-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 04/29/2019] [Indexed: 01/01/2023] Open
Abstract
Organ-specific colonization suggests that specific cell–cell recognition is essential. Yet, very little is known about this particular interaction. Moreover, tumor cell lodgement requires binding under shear stress, but not static, conditions. Here, we successfully isolate the metastatic populations of cancer stem/tumor-initiating cells (M-CSCs). We show that the M-CSCs tether more and roll slower than the non-metastatic (NM)-CSCs, thus resulting in the preferential binding to the peritoneal mesothelium under ascitic fluid shear stress. Mechanistically, this interaction is mediated by P-selectin expressed by the peritoneal mesothelium. Insulin-like growth factor receptor-1 carrying an uncommon non-sulfated sialyl-Lewisx (sLex) epitope serves as a distinct P-selectin binding determinant. Several glycosyltransferases, particularly α1,3-fucosyltransferase with rate-limiting activity for sLex synthesis, are highly expressed in M-CSCs. Tumor xenografts and clinical samples corroborate the relevance of these findings. These data advance our understanding on the molecular regulation of peritoneal metastasis and support the therapeutic potential of targeting the sLex-P-selectin cascade. Tumor cell in the peritoneum are often exposed to shear forces generated by ascitic flow during metastasis. Here, the authors show that metastatic cancer stem cells tether more and roll slower than the non-metastatic counterparts, and that sialyl-Lewisx -P-selectin axis mediates peritoneal metastasis.
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Affiliation(s)
- Shan-Shan Li
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong
| | - Carman K M Ip
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong
| | - Matthew Y H Tang
- Department of Mechanical Engineering, University of Hong Kong, Pokfulam, Hong Kong
| | - Maggie K S Tang
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong
| | - Yin Tong
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong
| | - Jiangwen Zhang
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong
| | - Ayon Ahmed Hassan
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong
| | - Abby S C Mak
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong
| | - Susan Yung
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Tak-Mao Chan
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Philip P Ip
- Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Cheuk Lun Lee
- Department of Obstetrics and Gynecology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Philip C N Chiu
- Department of Obstetrics and Gynecology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
| | - Leo Tsz On Lee
- Centre of Reproduction Development and Aging, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Hung-Cheng Lai
- Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 23561, Taiwan.,Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, Taipei, 23561, Taiwan
| | - Jin-Zhang Zeng
- State Key Laboratory of Cellular Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China
| | - Ho Cheung Shum
- Department of Mechanical Engineering, University of Hong Kong, Pokfulam, Hong Kong.
| | - Alice S T Wong
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong.
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Liu J, Liu Q, Wang Y, Liu M, Qi Y, Gao J, Lin B. Co‑expression of Lewis y antigen and CD147 in epithelial ovarian cancer is correlated with malignant progression and poor prognosis. Int J Mol Med 2019; 43:1687-1698. [PMID: 30816446 PMCID: PMC6414171 DOI: 10.3892/ijmm.2019.4103] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 02/12/2019] [Indexed: 11/05/2022] Open
Abstract
CD147 is a highly glycosylated transmembrane protein expressed on the surface of tumor cells. In the present study, the expression and clinical significance of the Lewis y antigen and CD147 in epithelial ovarian cancer (EOC) were analyzed, and the function and correlation in between the expression of Lewis y and CD147 were evaluated using immunohistochemical staining, reverse transcription‑quantitative polymerase chain reaction analysis, immunocytochemical staining, immunoprecipitation and western blotting. The results showed that the expression of CD147 was higher in EOC tissues and correlated with a higher tumor burden. Lewis y and CD147 exhibited similar expression patterns and their expression was positively correlated. The results of the immunofluorescence and immunoprecipitation experiments showed that Lewis y and CD147 colocalized in the cell membrane and cytoplasm. Lewis y antigen, but not Lewis x or sialyl Lewis x, was predominantly expressed in the highly glycosylated form of CD147. These changes occurred at the post‑transcriptional level. As an important component of CD147, Lewis y promoted CD147‑mediated cell adhesion and the expression of matrix metalloproteinase 2. In conclusion, Lewis y antigen and CD147 were significantly upregulated in ovarian tumors, and the altered expression of Lewis y may cause changes in CD147. The two molecules are associated with carcinogenesis and the development of ovarian cancer, and Lewis y antigen is a component of the CD147 structure.
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Affiliation(s)
- Juanjuan Liu
- Department of Obstetrics and Gynecology, China Medical University Shengjing Hospital, Shenyang, Liaoning 110004
| | - Qi Liu
- Department of Obstetrics and Gynecology, China Medical University Shengjing Hospital, Shenyang, Liaoning 110004
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Nanjing, Jiangsu 210008
| | - Yanyan Wang
- Department of Obstetrics and Gynecology, China Medical University Shengjing Hospital, Shenyang, Liaoning 110004
- Department of Obstetrics and Gynecology, Chaoyang Central Hospital, Chaoyang, Liaoning 122000, P.R. China
| | - Miao Liu
- Department of Obstetrics and Gynecology, China Medical University Shengjing Hospital, Shenyang, Liaoning 110004
| | - Yue Qi
- Department of Obstetrics and Gynecology, China Medical University Shengjing Hospital, Shenyang, Liaoning 110004
| | - Jian Gao
- Department of Obstetrics and Gynecology, China Medical University Shengjing Hospital, Shenyang, Liaoning 110004
| | - Bei Lin
- Department of Obstetrics and Gynecology, China Medical University Shengjing Hospital, Shenyang, Liaoning 110004
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Weil BR, Neelamegham S. Selectins and Immune Cells in Acute Myocardial Infarction and Post-infarction Ventricular Remodeling: Pathophysiology and Novel Treatments. Front Immunol 2019; 10:300. [PMID: 30873166 PMCID: PMC6400985 DOI: 10.3389/fimmu.2019.00300] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 02/05/2019] [Indexed: 12/21/2022] Open
Abstract
The glycosciences aim to understand the impact of extracellular and intracellular carbohydrate structures on biological function. These glycans primarily fall into three major groups: lipid-linked carbohydrates that are referred to as glycosphingolipids or simply glycolipids; relatively short carbohydrate chains that are often O- or N-linked to proteins yielding common glycoproteins; and extended linear polymeric carbohydrate structures that are referred to as glycosaminoglycans (GAGs). Whereas, the impact of such carbohydrate structures has been extensively examined in cancer biology, their role in acute and chronic heart disease is less studied. In this context, a growing body of evidence indicates that glycans play an important role in immune mediated cell recruitment to damaged heart tissue to initiate wound healing and repair after injury. This is particularly important following ischemia and reperfusion that occurs in the heart in the setting of acute myocardial infarction. Here, immune system-mediated repair of the damaged myocardium plays a critical role in determining post-infarction ventricular remodeling, cardiac function, and patient outcome. Further, alterations in immune cell activity can promote the development of heart failure. The present review summarizes our current understanding of the phases of immune-mediated repair following myocardial infarction. It discusses what is known regarding glycans in mediating the recruitment of circulating immune cells during the early inflammatory stage of post-infarction repair, with focus on the selectin family of adhesion molecules. It offers future directions for research aimed at utilizing our knowledge of mechanisms underlying immune cell recruitment to either modulate leukocyte recruitment to the injured tissue or enhance the targeted delivery of biologic therapeutics such as stem cells in an attempt to promote repair of the damaged heart.
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Affiliation(s)
- Brian R Weil
- Department of Physiology and Biophysics, University at Buffalo, State University of New York, Buffalo, NY, United States
| | - Sriram Neelamegham
- Department of Medicine, University at Buffalo, State University of New York, Buffalo, NY, United States.,Department of Chemical & Biological Engineering, University at Buffalo, State University of New York, Buffalo, NY, United States
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Epigenetic silencing of the synthesis of immunosuppressive Siglec ligand glycans by NF-κB/EZH2/YY1 axis in early-stage colon cancers. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2019; 1862:173-183. [PMID: 30716533 DOI: 10.1016/j.bbagrm.2019.01.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 12/07/2018] [Accepted: 01/07/2019] [Indexed: 12/12/2022]
Abstract
Normal colonic epithelial cells express sialyl 6-sulfo Lewisx and disialyl Lewisa on their cell surface, which are ligands for the immunosuppressive molecule Siglec-7. Expression of these normal glycans is frequently lost upon malignant transformation by silencing DTDST and ST6GalNAc6 at the early stage of colorectal carcinogenesis, and leads to production of inflammatory mediators that facilitate carcinogenesis. Indeed, by querying The Cancer Genome Atlas datasets, we confirmed that the level of DTDST or ST6GalNAc6 mRNA is substantially decreased at the early stage of colorectal carcinogenesis. Cultured colon cancer cell lines were used in this study including DLD-1, HT-29, LS174T and SW620. Their promoter regions were strongly marked by repressive mark H3K27me3, catalyzed by EZH2 that was markedly upregulated in early stage of colorectal carcinogenesis. Suppression of EZH2 substantially downregulated H3K27me3 mark and upregulated DTDST and ST6GalNAc6 as well as expression of normal glycans and Siglec-binding activities. Transcription factor YY1 was vital for the recruitment of PRC2-containing EZH2 to both promoters. Inhibition of NF-κB substantially reduced EZH2 transcription and restored their mRNAs as well as the production of normal Siglec ligand glycans in the results obtained from in vitro studies on cultured colon cancer cell lines. These findings provide a putative mechanism for promotion of carcinogenesis by loss of immunosuppressive molecules by epigenetic silencing through NF-κB-mediated EZH2/YY1 axis.
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Tumor-infiltrating Neutrophils is Prognostic and Predictive for Postoperative Adjuvant Chemotherapy Benefit in Patients With Gastric Cancer. Ann Surg 2019; 267:311-318. [PMID: 27763900 DOI: 10.1097/sla.0000000000002058] [Citation(s) in RCA: 145] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE This study was aimed to investigate the prognostic value of tumor-infiltrating neutrophils (TINs) and to generate a predictive model to refine postoperative risk stratification system for patients with gastric cancer. BACKGROUND TIN presents in various malignant tumors, but its clinical significance in gastric cancer remains obscure. METHODS The study enrolled 3 independent sets of patients with gastric cancer from 2 institutional medical centers of China. TIN was estimated by immunohistochemical staining of CD66b, and its relationship with clinicopathological features and clinical outcomes were evaluated. Prognostic accuracies were evaluated by C-index and Akaike information criterion. RESULTS TINs in gastric cancer tissues ranged from 0 to 192 cells/high magnification filed (HPF), 0 to 117 cells/HPF, and 0 to 142 cells/HPF in the training, testing, and validation sets, respectively. TINs were negatively correlated with lymph node classification (P = 0.007, P = 0.041, and P = 0.032, respectively) and tumor stage (P = 0.019, P = 0.013, and P = 0.025, respectively) in the 3 sets. Moreover, multivariate analysis identified TINs and tumor node metastasis (TNM) stage as 2 independent prognostic factors for overall survival. Incorporation of TINs into well-established TNM system generated a predictive model that shows better predictive accuracy for overall survival. More importantly, patients with higher TINs were prone to overall survival benefit from postoperative adjuvant chemotherapy. These results were validated in the independent testing and validation sets. CONCLUSIONS TIN in gastric cancer was identified as an independent prognostic factor, which could be incorporated into standard TNM staging system to refine risk stratification and predict for overall survival benefit from postoperative chemotherapy in patients with gastric cancer.
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Xu J, Seung-Young Lee S, Seo H, Pang L, Jun Y, Zhang RY, Zhang ZY, Kim P, Lee W, Kron SJ, Yeo Y. Quinic Acid-Conjugated Nanoparticles Enhance Drug Delivery to Solid Tumors via Interactions with Endothelial Selectins. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2018; 14:e1803601. [PMID: 30411856 PMCID: PMC6361670 DOI: 10.1002/smll.201803601] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 10/11/2018] [Indexed: 05/26/2023]
Abstract
Current nanoparticle (NP) drug carriers mostly depend on the enhanced permeability and retention (EPR) effect for selective drug delivery to solid tumors. However, in the absence of a persistent EPR effect, the peritumoral endothelium can function as an access barrier to tumors and negatively affect the effectiveness of NPs. In recognition of the peritumoral endothelium as a potential barrier in drug delivery to tumors, poly(lactic-co-glycolic acid) (PLGA) NPs are modified with a quinic acid (QA) derivative, synthetic mimic of selectin ligands. QA-decorated NPs (QA-NP) interact with human umbilical vein endothelial cells expressing E-/P-selectins and induce transient increase in endothelial permeability to translocate across the layer. QA-NP reach selectin-upregulated tumors, achieving greater tumor accumulation and paclitaxel (PTX) delivery than polyethylene glycol-decorated NPs (PEG-NP). PTX-loaded QA-NP show greater anticancer efficacy than Taxol or PTX-loaded PEG-NP at the equivalent PTX dose in different animal models and dosing regimens. Repeated dosing of PTX-loaded QA-NP for two weeks results in complete tumor remission in 40-60% of MDA-MB-231 tumor-bearing mice, while those receiving control treatments succumb to death. QA-NP can exploit the interaction with selectin-expressing peritumoral endothelium and deliver anticancer drugs to tumors to a greater extent than the level currently possible with the EPR effect.
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Affiliation(s)
- Jun Xu
- Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA,
| | - Steve Seung-Young Lee
- Ludwig Center for Metastasis Research, The University of Chicago, 5758 South Maryland Avenue, MC 9006, and Department of Molecular Genetics and Cellular Biology, The University of Chicago, 929 East 57th Street, GCIS W519, Chicago, IL 60637, USA
| | - Howon Seo
- Graduate School of Nanoscience and Technology and KAIST Institute for Health Science and Technology, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Liang Pang
- Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 201203, People’s Republic of China
| | - Yearin Jun
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Ruo-Yu Zhang
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA
| | - Zhong-Yin Zhang
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA
| | - Pilhan Kim
- Graduate School of Nanoscience and Technology and KAIST Institute for Health Science and Technology, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea; Graduate School of Medical Science and Engineering, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Wooin Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Stephen J. Kron
- Ludwig Center for Metastasis Research, The University of Chicago, 5758 South Maryland Avenue, MC 9006, and Department of Molecular Genetics and Cellular Biology, The University of Chicago, 929 East 57th Street, GCIS W519, Chicago, IL 60637, USA
| | - Yoon Yeo
- Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA, ; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA
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Ohshio G, Yamaki K, Imamura T, Suwa H, Chang CY, Wada H, Sueno Y, Imamura M. Distribution of the Carbohydrate Antigens, Du-Pan-2 and Ca19-9, in Tumors of the Lung. TUMORI JOURNAL 2018; 81:67-73. [PMID: 7754546 DOI: 10.1177/030089169508100116] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Aims and background The carbohydrate chains of malignant cells appear to be related to oncofetal differentiation. The serum levels of CA19-9 have been reported to be evaluated in some patients with lung carcinomas, however, the distribution of carbohydrate antigens were not precisely described. We have investigated in this study the distribution of DU-PAN-2 and CA19-9 antigens in lung tumors. Methods Ninety five specimens of lung tumors were selected from surgical specimens. The expression of DU-PAN-2 and CA19-9 were studied by immunohystochemical techniques. The relationship between the expression of these antigens and the classification or the differentiation degree of the tumors were examined. Results DU-PAN-2 or CA19-9 antigens were detected in 41 (54%) and 45 (59%) cases of the 76 malignant epithelial tumors investigated. These antigens were detected in all types of malignant epithelial tumors, including squamous cell carcinomas, where they were mainly localized to the entire cell surface of malignant cells. In adenocarcinomas, large cell carcinomas and small cell carcinomas, however, these antigens were commonly detected both on the cell membrane and in the cytoplasm. There was positive correlation between the degree of differentiation and DU-PAN-2, but not CA19-9 expression. Among the non-epithelial tumors investigated, those antigens were detected in pulmonary blastomas but not in mesotheliomas. Conclusions Immunohistochemical studies for DU-PAN-2 and CA19-9 are useful for defining characteristics of the lung tumors. DU-PAN-2 could be a marker for differentiating between malignant epithelial tumors and mesotheliomas.
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Affiliation(s)
- G Ohshio
- Department of Surgery and Thoracic Surgery, Kyoto University, Japan
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Lee CH, Zhang HH, Singh SP, Koo L, Kabat J, Tsang H, Singh TP, Farber JM. C/EBPδ drives interactions between human MAIT cells and endothelial cells that are important for extravasation. eLife 2018; 7:32532. [PMID: 29469805 PMCID: PMC5869018 DOI: 10.7554/elife.32532] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 02/21/2018] [Indexed: 12/14/2022] Open
Abstract
Many mediators and regulators of extravasation by bona fide human memory-phenotype T cells remain undefined. Mucosal-associated invariant T (MAIT) cells are innate-like, antibacterial cells that we found excelled at crossing inflamed endothelium. They displayed abundant selectin ligands, with high expression of FUT7 and ST3GAL4, and expressed CCR6, CCR5, and CCR2, which played non-redundant roles in trafficking on activated endothelial cells. MAIT cells selectively expressed CCAAT/enhancer-binding protein delta (C/EBPδ). Knockdown of C/EBPδ diminished expression of FUT7, ST3GAL4 and CCR6, decreasing MAIT cell rolling and arrest, and consequently the cells' ability to cross an endothelial monolayer in vitro and extravasate in mice. Nonetheless, knockdown of C/EBPδ did not affect CCR2, which was important for the step of transendothelial migration. Thus, MAIT cells demonstrate a program for extravasastion that includes, in part, C/EBPδ and C/EBPδ-regulated genes, and that could be used to enhance, or targeted to inhibit T cell recruitment into inflamed tissue.
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Affiliation(s)
- Chang Hoon Lee
- Inflammation Biology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
| | - Hongwei H Zhang
- Inflammation Biology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
| | - Satya P Singh
- Inflammation Biology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
| | - Lily Koo
- Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
| | - Juraj Kabat
- Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
| | - Hsinyi Tsang
- Inflammation Biology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
| | - Tej Pratap Singh
- Inflammation Biology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
| | - Joshua M Farber
- Inflammation Biology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
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Silva M, Videira PA, Sackstein R. E-Selectin Ligands in the Human Mononuclear Phagocyte System: Implications for Infection, Inflammation, and Immunotherapy. Front Immunol 2018; 8:1878. [PMID: 29403469 PMCID: PMC5780348 DOI: 10.3389/fimmu.2017.01878] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Accepted: 12/08/2017] [Indexed: 12/20/2022] Open
Abstract
The mononuclear phagocyte system comprises a network of circulating monocytes and dendritic cells (DCs), and “histiocytes” (tissue-resident macrophages and DCs) that are derived in part from blood-borne monocytes and DCs. The capacity of circulating monocytes and DCs to function as the body’s first-line defense against offending pathogens greatly depends on their ability to egress the bloodstream and infiltrate inflammatory sites. Extravasation involves a sequence of coordinated molecular events and is initiated by E-selectin-mediated deceleration of the circulating leukocytes onto microvascular endothelial cells of the target tissue. E-selectin is inducibly expressed by cytokines (tumor necrosis factor-α and IL-1β) on inflamed endothelium, and binds to sialofucosylated glycan determinants displayed on protein and lipid scaffolds of blood cells. Efficient extravasation of circulating monocytes and DCs to inflamed tissues is crucial in facilitating an effective immune response, but also fuels the immunopathology of several inflammatory disorders. Thus, insights into the structural and functional properties of the E-selectin ligands expressed by different monocyte and DC populations is key to understanding the biology of protective immunity and the pathobiology of several acute and chronic inflammatory diseases. This review will address the role of E-selectin in recruitment of human circulating monocytes and DCs to sites of tissue injury/inflammation, the structural biology of the E-selectin ligands expressed by these cells, and the molecular effectors that shape E-selectin ligand cell-specific display. In addition, therapeutic approaches targeting E-selectin receptor/ligand interactions, which can be used to boost host defense or, conversely, to dampen pathological inflammatory conditions, will also be discussed.
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Affiliation(s)
- Mariana Silva
- Department of Dermatology, Harvard Skin Disease Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.,Program of Excellence in Glycosciences, Harvard Medical School, Boston, MA, United States
| | - Paula A Videira
- UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Lisboa, Portugal.,Professionals and Patient Associations International Network (CDG & Allies - PPAIN), Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Lisboa, Portugal
| | - Robert Sackstein
- Department of Dermatology, Harvard Skin Disease Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.,Program of Excellence in Glycosciences, Harvard Medical School, Boston, MA, United States.,Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
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48
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Abstract
Tumor-associated gangliosides play important roles in regulation of signal transduction induced by growth-factor receptors including EGFR, FGFR, HGF and PDGFR in a specific microdomain called glycosynapse in the cancer cell membranes, and in interaction with glycan recognition molecules involved in cell adhesion and immune regulation including selectins and siglecs. As the genes involved in the synthesis and degradation of tumor-associated gangliosides were identified, biological functions became clearer from the experimental results employing forced overexpression and/or knockdown/knockout of the genes. Studies on the regulatory mechanisms for their expression also achieved great advancements. Epigenetic silencing of glycan-related genes is a dominant mechanism in glycan alteration at early stages of carcinogenesis. Development of hypoxia resistance involving activation of a transcription factor HIF, and acquisition of cancer stem cell-like characteristics through epithelial-mesenchymal transition are important mechanisms for glycan modulations in the later stages of cancer progression. In the initial stages of studies, the gangliosides which specifically appear in cancers attracted attention under the name of tumor-associated gangliosides. However, it became apparent that not only the cancer-associated gangliosides but also the normal gangliosides present in nonmalignant cells and tissues perform important biological functions, and some of them tend to disappear in cancer cells resulting in the loss of the physiological functions, and this sometimes facilitates progression of cancers.
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49
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Liu YB, Yao W, Meng S, Meng XB, Li ZJ, Lou QH. A novel cobalt(0) alkyne complex assisted “capture and release” strategy for oligosaccharide rapid assembly. Org Chem Front 2018. [DOI: 10.1039/c8qo00324f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Abstract
Linear and branched penta-mannosides were conveniently synthesized via a resin assisted “capture and release” purification strategy.
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Affiliation(s)
- Yan-Bo Liu
- The State Key Laboratory of Natural and Biomimetic Drugs of Peking University, School of Pharmaceutical Sciences
- Beijing 100191
- People's Republic of China
| | - Wang Yao
- The State Key Laboratory of Natural and Biomimetic Drugs of Peking University, School of Pharmaceutical Sciences
- Beijing 100191
- People's Republic of China
| | - Shuai Meng
- The State Key Laboratory of Natural and Biomimetic Drugs of Peking University, School of Pharmaceutical Sciences
- Beijing 100191
- People's Republic of China
| | - Xiang-Bao Meng
- The State Key Laboratory of Natural and Biomimetic Drugs of Peking University, School of Pharmaceutical Sciences
- Beijing 100191
- People's Republic of China
| | - Zhong-Jun Li
- The State Key Laboratory of Natural and Biomimetic Drugs of Peking University, School of Pharmaceutical Sciences
- Beijing 100191
- People's Republic of China
| | - Qing-Hua Lou
- The State Key Laboratory of Natural and Biomimetic Drugs of Peking University, School of Pharmaceutical Sciences
- Beijing 100191
- People's Republic of China
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Kim M, Yoo SJ, Kang SW, Kwon J, Choi I, Lee CH. TNFα and IL-1β in the synovial fluid facilitate mucosal-associated invariant T (MAIT) cell migration. Cytokine 2017; 99:91-98. [DOI: 10.1016/j.cyto.2017.07.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 07/05/2017] [Accepted: 07/12/2017] [Indexed: 12/17/2022]
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