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Bastian K, Orozco‐Moreno M, Thomas H, Hodgson K, Visser EA, Rossing E, Pijnenborg JFA, Eerden N, Wilson L, Saravannan H, Hanley O, Grimsley G, Frame F, Peng Z, Knight B, McCullagh P, McGrath J, Crundwell M, Harries L, Maitland NJ, Heer R, Wang N, Goddard‐Borger ED, Guerrero RH, Boltje TJ, Drake RR, Scott E, Elliott DJ, Munkley J. FUT8 Is a Critical Driver of Prostate Tumour Growth and Can Be Targeted Using Fucosylation Inhibitors. Cancer Med 2025; 14:e70959. [PMID: 40387385 PMCID: PMC12086987 DOI: 10.1002/cam4.70959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 04/20/2025] [Accepted: 04/29/2025] [Indexed: 05/20/2025] Open
Abstract
BACKGROUND An unmet clinical need requires the discovery of new treatments for men facing advanced prostate cancer. Aberrant glycosylation is a universal feature of cancer cells and plays a key role in tumour growth, immune evasion and metastasis. Alterations in tumour glycosylation are closely associated with prostate cancer progression, making glycans promising therapeutic targets. Fucosyltransferase 8 (FUT8) drives core fucosylation by adding α1,6-fucose to the innermost GlcNAc residue on N-glycans. While FUT8 is recognised as a crucial factor in cancer progression, its role in prostate cancer remains poorly understood. METHODS & RESULTS Here, we demonstrate using multiple independent clinical cohorts that FUT8 is upregulated in high grade and metastatic prostate tumours, and in the blood of prostate cancer patients with aggressive disease. Using novel tools, including PhosL lectin immunofluorescence and N-glycan MALDI mass spectrometry imaging (MALDI-MSI), we find FUT8 underpins the biosynthesis of malignant core fucosylated N-glycans in prostate cancer cells and using both in vitro and in vivo models, we find FUT8 promotes prostate tumour growth, cell motility and invasion. Mechanistically we show FUT8 regulates the expression of genes and signalling pathways linked to prostate cancer progression. Furthermore, we find that fucosylation inhibitors can inhibit the activity of FUT8 in prostate cancer to suppress the growth of prostate tumours. CONCLUSIONS Our study cements FUT8-mediated core fucosylation as an important driver of prostate cancer progression and suggests targeting FUT8 activity for prostate cancer therapy as an exciting area to explore.
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Affiliation(s)
- Kayla Bastian
- Newcastle University Centre for CancerNewcastle University Institute of BiosciencesNewcastleUK
| | - Margarita Orozco‐Moreno
- Newcastle University Centre for CancerNewcastle University Institute of BiosciencesNewcastleUK
| | - Huw Thomas
- Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Paul O'gorman BuildingNewcastle UniversityNewcastle upon TyneUK
| | - Kirsty Hodgson
- Newcastle University Centre for CancerNewcastle University Institute of BiosciencesNewcastleUK
| | - Eline A. Visser
- Synthetic Organic Chemistry, Institute for Molecules and MaterialsRadboud UniversityNijmegenthe Netherlands
| | - Emiel Rossing
- Synthetic Organic Chemistry, Institute for Molecules and MaterialsRadboud UniversityNijmegenthe Netherlands
| | | | | | - Laura Wilson
- Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Paul O'gorman BuildingNewcastle UniversityNewcastle upon TyneUK
| | - Hasvini Saravannan
- Newcastle University Centre for CancerNewcastle University Institute of BiosciencesNewcastleUK
| | - Oliver Hanley
- Newcastle University Centre for CancerNewcastle University Institute of BiosciencesNewcastleUK
| | - Grace Grimsley
- Department of Cell and Molecular PharmacologyMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Fiona Frame
- Cancer Research Unit, Department of BiologyUniversity of YorkNorth YorkshireUK
| | - Ziqian Peng
- Newcastle University Centre for CancerNewcastle University Institute of BiosciencesNewcastleUK
| | - Bridget Knight
- NIHR Exeter Clinical Research FacilityRoyal Devon and Exeter NHS Foundation TrustExeterUK
| | - Paul McCullagh
- Department of PathologyRoyal Devon and Exeter NHS Foundation TrustExeterUK
| | - John McGrath
- Exeter Surgical Health Services Research UnitRoyal Devon and Exeter NHS Foundation TrustExeterUK
| | - Malcolm Crundwell
- Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and HealthUniversity of ExeterExeterUK
| | - Lorna Harries
- Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and HealthUniversity of ExeterExeterUK
| | - Norman J. Maitland
- Cancer Research Unit, Department of BiologyUniversity of YorkNorth YorkshireUK
| | - Rakesh Heer
- Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Paul O'gorman BuildingNewcastle UniversityNewcastle upon TyneUK
| | - Ning Wang
- The Mellanby Centre for Musculoskeletal Research, Division of Clinical MedicineThe University of SheffieldSheffieldUK
- Leicester Cancer Research Centre, Department of Genetics, Genomics, and Cancer SciencesUniversity of LeicesterLeicesterUK
| | - Ethan D. Goddard‐Borger
- The Walter and Eliza Hall Institute of Medical ResearchParkvilleVictoriaAustralia
- Department of Medical BiologyUniversity of MelbourneParkvilleVictoriaAustralia
| | - Ramon Hurtado Guerrero
- University of ZaragozaZaragozaSpain
- Copenhagen Center for Glycomics, Department of Cellular and Molecular MedicineUniversity of CopenhagenCopenhagenDenmark
| | - Thomas J. Boltje
- Synthetic Organic Chemistry, Institute for Molecules and MaterialsRadboud UniversityNijmegenthe Netherlands
| | - Richard R. Drake
- Department of Cell and Molecular PharmacologyMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Emma Scott
- Newcastle University Centre for CancerNewcastle University Institute of BiosciencesNewcastleUK
| | - David J. Elliott
- Newcastle University Centre for CancerNewcastle University Institute of BiosciencesNewcastleUK
| | - Jennifer Munkley
- Newcastle University Centre for CancerNewcastle University Institute of BiosciencesNewcastleUK
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Xue K, Bai Y, Han Y, Yao C, Zhao Z, Liang D, Lu F, Jin Y, Song J. Ginsenoside Rg6 Improves Cisplatin Resistance in Epithelial Ovarian Cancer Cells via Suppressing Fucosylation and Inducing Autophagy. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2025; 53:621-646. [PMID: 40145279 DOI: 10.1142/s0192415x25500247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/28/2025]
Abstract
Platinum-based chemotherapy remains a mainstay of clinical practice in the standard treatment of epithelial ovarian cancer (EOC). Most patients who receive this treatment, however, develop relapse and drug resistance. Ginsenoside Rg6 (G-Rg6), one of the anticarcinogenic active components in the American ginseng berry, may hold promise in the adjuvant chemotherapy of EOC. In this study, the correlation between fucosylation and cisplatin (cDDP) resistance in EOC cells was validated by gene expression profile analysis and lectin blot. We found that G-Rg6 derived from the American ginseng berry inhibits the cell viability and protein fucosylation of cDDP-resistant EOC cells. G-Rg6-induced G2/M-cell cycle arrest was proven to result from the autophagy of cDDP-resistant EOC cells. In addition, we observed that G-Rg6 initiates autophagy in cDDP-resistant EOC cells by inhibiting the GRB2-ERK1/2-mTOR axis, and that high concentration of G-Rg6 treatment leads to cell apoptosis. G-Rg6 also enhances cDDP uptake in A2780CP cells by promoting CTR1 expression and suppressing its core fucosylation. Therapies combining cDDP and G-Rg6 display higher efficacy in inhibiting the cDDP-resistant EOC cells in comparison with the sole application of cDDP, exhibiting strong potential for clinical application. G-Rg6 derived from the American ginseng berry can improve cDDP resistance in EOC cells via suppressing fucosylation and inducing autophagy, suggesting its potential in the adjuvant chemotherapy of EOC patients.
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Affiliation(s)
- Kai Xue
- College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P. R. China
| | - Yun Bai
- School of Public Health, Dalian Medical University, Dalian, Liaoning 116044, P. R. China
| | - Yufei Han
- The Second Hospital of Dalian Medical University, Dalian, Liaoning 116023, P. R. China
| | - Chuanxiang Yao
- School of Pharmaceutical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P. R. China
| | - Zhenzhe Zhao
- Department of Anesthesiology, Dalian Medical University, Dalian, Liaoning 116044, P. R. China
| | - Dongyang Liang
- School of Public Health, Dalian Medical University, Dalian, Liaoning 116044, P. R. China
| | - Feiyu Lu
- School of Public Health, Dalian Medical University, Dalian, Liaoning 116044, P. R. China
| | - Yinping Jin
- Institute of Biological and Pharmaceutical Engineering, Jilin Agricultural Science and Technology University, Jilin 132101, P. R. China
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, Jilin 130112, P. R. China
| | - Jiazhe Song
- College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P. R. China
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Xiong Z, Huang Y, Cao S, Huang X, Zhang H. A new strategy for the treatment of advanced ovarian cancer: utilizing nanotechnology to regulate the tumor microenvironment. Front Immunol 2025; 16:1542326. [PMID: 40013141 PMCID: PMC11860879 DOI: 10.3389/fimmu.2025.1542326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 01/30/2025] [Indexed: 02/28/2025] Open
Abstract
Advanced ovarian cancer (AOC) is prone to recurrence, which can be attributed to drug resistance. Drug resistance may be related to the tumor microenvironment (TME), including the immune and non-immune TME. In the immune TME, the immune effector cells such as dendritic cells (DCs), M1-like tumor-associated macrophages (M1-TAMs), and T cells are inhibited. In contrast, immunosuppressive cells such as M2-like tumor-associated macrophages (M2-TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) are activated. These changes make it difficult to produce immune effects and affect the efficacy of chemo-immunotherapy. In the non-immune TME, mechanisms such as apoptosis inhibition, DNA damage response (DDR), and epithelial-mesenchymal transition (EMT) can promote tumor growth, metastasis, and drug resistance. Despite the challenges posed by the TME in the treatment of AOC, the unique biological advantages of nanoparticles (NPs) make it possible to regulate the TME. NPs can stimulate the immune responses of M1-TAMs, DCs, and T cells while reducing the infiltration of immune suppressive cells such as M2-TAMs and Tregs, thereby regulating the AOC immune TME. In addition, NPs can regulate the non-immune TME by reducing apoptosis in AOC cells, inhibiting homologous recombination (HR) repair, reversing EMT, and achieving the effect of reversing drug resistance. In summary, the application of NPs provides some new venues for clinical treatment in AOC.
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Affiliation(s)
- Zixuan Xiong
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
| | - Yichun Huang
- Department of Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Shulong Cao
- Department of Pathology, Songzi People’s Hospital, Jingzhou, China
| | - Xuqun Huang
- Department of Medical Oncology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Huangshi, China
| | - Haiyuan Zhang
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
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Pan Q, Zhang XL. Roles of core fucosylation modification in immune system and diseases. CELL INSIGHT 2025; 4:100211. [PMID: 39624801 PMCID: PMC11609374 DOI: 10.1016/j.cellin.2024.100211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 10/01/2024] [Accepted: 10/02/2024] [Indexed: 01/04/2025]
Abstract
Core fucosylation, catalyzed by α1,6-fucosyltransferase (FUT8), is an important N-glycosylation modification process that attaches a fucose residue via an α1,6-linkage to the core N-acetylglucosamine of N-glycans in mammals. Research over the past three decades has revealed the critical role of FUT8-mediated core fucosylation modification in various physiological and pathological processes, including cell growth, adhesion, receptor activation, antibody-dependent cellular cytotoxicity (ADCC), tumor metastasis and infections. This review discusses the immune system function involving FUT8 and the mechanisms by which core fucosylation regulates immunity and contributes to disease. A deeper understanding of these mechanisms can provide insights into cellular biology and suggest new therapeutic approaches and targets for related diseases.
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Affiliation(s)
- Qiu Pan
- Hubei Province Key Laboratory of Allergy and Immunology, Department of Allergy Zhongnan Hospital of Wuhan University, Department of Immunology Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan, 430071, China
- State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Wuhan University School of Medicine, Wuhan, 430071, China
| | - Xiao-Lian Zhang
- Hubei Province Key Laboratory of Allergy and Immunology, Department of Allergy Zhongnan Hospital of Wuhan University, Department of Immunology Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan, 430071, China
- State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Wuhan University School of Medicine, Wuhan, 430071, China
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Dey Bhowmik A, Shaw P, Gopinatha Pillai MS, Rao G, Dwivedi SKD. Evolving landscape of detection and targeting miRNA/epigenetics for therapeutic strategies in ovarian cancer. Cancer Lett 2024; 611:217357. [PMID: 39615646 PMCID: PMC12119979 DOI: 10.1016/j.canlet.2024.217357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 11/22/2024] [Accepted: 11/25/2024] [Indexed: 12/14/2024]
Abstract
Ovarian cancer (OC) accounts for the highest mortality rates among all gynecologic malignancies. The high mortality of OC is often associated with delayed detection, prolonged latency, enhanced metastatic potential, acquired drug resistance, and frequent recurrence. This review comprehensively explores key aspects of OC, including cancer diagnosis, mechanisms of disease resistance, and the pivotal role of epigenetic regulation, particularly by microRNAs (miRs) in cancer progression. We highlight the intricate regulatory mechanisms governing miR expression within the context of OC and the current status of epigenetic advancement in the therapeutic development and clinical trial progression. Through network analysis we elucidate the regulatory interactions between dysregulated miRs in OC and their targets which are involved in different signaling pathways. By exploring these interconnected facets and critical analysis, we endeavor to provide a nuanced understanding of the molecular dynamics underlying OC, its detection and shedding light on potential avenues for miRs and epigenetics-based therapeutic intervention and management strategies.
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Affiliation(s)
- Arpan Dey Bhowmik
- Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Pallab Shaw
- Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Mohan Shankar Gopinatha Pillai
- Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Geeta Rao
- Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Shailendra Kumar Dhar Dwivedi
- Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
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Chen X, Zhang D, Ou H, Su J, Wang Y, Zhou F. Bulk and single-cell RNA sequencing analyses coupled with multiple machine learning to develop a glycosyltransferase associated signature in colorectal cancer. Transl Oncol 2024; 49:102093. [PMID: 39217850 PMCID: PMC11402624 DOI: 10.1016/j.tranon.2024.102093] [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: 01/21/2024] [Revised: 07/10/2024] [Accepted: 08/11/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND This study aims to identify key glycosyltransferases (GTs) in colorectal cancer (CRC) and establish a robust prognostic signature derived from GTs. METHODS Utilizing the AUCell, UCell, singscore, ssgsea, and AddModuleScore algorithms, along with correlation analysis, we redefined genes related to GTs in CRC at the single-cell RNA level. To improve risk model accuracy, univariate Cox and lasso regression were employed to discover a more clinically subset of GTs in CRC. Subsequently, the efficacy of seven machine learning algorithms for CRC prognosis was assessed, focusing on survival outcomes through nested cross-validation. The model was then validated across four independent external cohorts, exploring variations in the tumor microenvironment (TME), response to immunotherapy, mutational profiles, and pathways of each risk group. Importantly, we identified potential therapeutic agents targeting patients categorized into the high-GARS group. RESULTS In our research, we classified CRC patients into distinct subgroups, each exhibiting variations in prognosis, clinical characteristics, pathway enrichments, immune infiltration, and immune checkpoint genes expression. Additionally, we established a Glycosyltransferase-Associated Risk Signature (GARS) based on machine learning. GARS surpasses traditional clinicopathological features in both prognostic power and survival prediction accuracy, and it correlates with higher malignancy levels, providing valuable insights into CRC patients. Furthermore, we explored the association between the risk score and the efficacy of immunotherapy. CONCLUSION A prognostic model based on GTs was developed to forecast the response to immunotherapy, offering a novel approach to CRC management.
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Affiliation(s)
- Xin Chen
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China; Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan, PR China; Hubei Clinical Cancer Study Center, Zhongnan Hospital, Wuhan University, PR China
| | - Dan Zhang
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China; Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan, PR China; Hubei Clinical Cancer Study Center, Zhongnan Hospital, Wuhan University, PR China
| | - Haibin Ou
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China; Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan, PR China; Hubei Clinical Cancer Study Center, Zhongnan Hospital, Wuhan University, PR China
| | - Jing Su
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China; Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan, PR China; Hubei Clinical Cancer Study Center, Zhongnan Hospital, Wuhan University, PR China
| | - You Wang
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China; Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan, PR China; Hubei Clinical Cancer Study Center, Zhongnan Hospital, Wuhan University, PR China.
| | - Fuxiang Zhou
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China; Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan, PR China; Hubei Clinical Cancer Study Center, Zhongnan Hospital, Wuhan University, PR China.
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Alvear-Hernandez NP, Hernández-Ramírez VI, Villegas-Pineda JC, Osorio-Trujillo JC, Guzmán-Mendoza JJ, Gallardo-Rincón D, Toledo-Leyva A, Talamás-Rohana P. Overexpression of Fut 2, 4, and 8, and nuclear localization of Fut 4 in ovarian cancer cell lines induced by ascitic fluids from epithelial ovarian cancer patients. Cell Biol Int 2024; 48:610-625. [PMID: 38263584 DOI: 10.1002/cbin.12132] [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: 03/23/2023] [Revised: 12/21/2023] [Accepted: 01/05/2024] [Indexed: 01/25/2024]
Abstract
Fucosyltransferases (Fut) regulate the fucosylation process associated with tumorogenesis in different cancer types. Ascitic fluid (AF) from patients diagnosed with advanced stage of epithelial ovarian cancer (EOC) is considered as a dynamic tumor microenvironment associated with poor prognosis. Previous studies from our laboratory showed increased fucosylation in SKOV-3 and OVCAR-3, cancer-derived cell lines, when these cells were incubated with AFs derived from patients diagnosed with EOC. In the present work we studied three fucosyltransferases (Fut 2, Fut 4, and Fut 8) in SKOV-3, OVCAR-3 and CAOV-3 cell lines in combination with five different AFs from patients diagnosed with this disease, confirming that all tested AFs increased fucosylation. Then, we demonstrate that mRNAs of these three enzymes were overexpressed in the three cell lines under treatment with AFs. SKOV-3 showed the higher overexpression of Fut 2, Fut 4, and Fut 8 in comparison with the control condition. We further confirmed, in the SKOV-3 cell line, by endpoint PCR, WB, and confocal microscopy, that the three enzymes were overexpressed, being Fut 4 the most overexpressed enzyme compared to Fut 2 and Fut 8. These enzymes were concentrated in vesicular structures with a homogeneous distribution pattern throughout the cytoplasm. Moreover, we found that among the three enzymes, only Fut 4 was located inside the nuclei. The nuclear location of Fut 4 was confirmed for the three cell lines. These results allow to propose Fut 2, Fut 4, and Fut 8 as potential targets for EOC treatment or as diagnostic tools for this disease.
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Affiliation(s)
- Nayely Paulina Alvear-Hernandez
- Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, Gustavo A Madero, Mexico
| | | | - Julio César Villegas-Pineda
- Departamento de Microbiología y, Patología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, México
| | - Juan Carlos Osorio-Trujillo
- Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, Gustavo A Madero, Mexico
| | - José Jesús Guzmán-Mendoza
- Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, Gustavo A Madero, Mexico
| | | | - Alfredo Toledo-Leyva
- Unidad de Investigación en Virología y Cáncer, Hospital Infantil de México Federico Gómez, Instituto Nacional de Salud, Ciudad de México, Mexico
| | - Patricia Talamás-Rohana
- Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, Gustavo A Madero, Mexico
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Alam S, Giri PK. Novel players in the development of chemoresistance in ovarian cancer: ovarian cancer stem cells, non-coding RNA and nuclear receptors. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2024; 7:6. [PMID: 38434767 PMCID: PMC10905178 DOI: 10.20517/cdr.2023.152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 02/03/2024] [Accepted: 02/22/2024] [Indexed: 03/05/2024]
Abstract
Ovarian cancer (OC) ranks as the fifth leading factor for female mortality globally, with a substantial burden of new cases and mortality recorded annually. Survival rates vary significantly based on the stage of diagnosis, with advanced stages posing significant challenges to treatment. OC is primarily categorized as epithelial, constituting approximately 90% of cases, and correct staging is essential for tailored treatment. The debulking followed by chemotherapy is the prevailing treatment, involving platinum-based drugs in combination with taxanes. However, the efficacy of chemotherapy is hindered by the development of chemoresistance, both acquired during treatment (acquired chemoresistance) and intrinsic to the patient (intrinsic chemoresistance). The emergence of chemoresistance leads to increased mortality rates, with many advanced patients experiencing disease relapse shortly after initial treatment. This review delves into the multifactorial nature of chemoresistance in OC, addressing mechanisms involving transport systems, apoptosis, DNA repair, and ovarian cancer stem cells (OCSCs). While previous research has identified genes associated with these mechanisms, the regulatory roles of non-coding RNA (ncRNA) and nuclear receptors in modulating gene expression to confer chemoresistance have remained poorly understood and underexplored. This comprehensive review aims to shed light on the genes linked to different chemoresistance mechanisms in OC and their intricate regulation by ncRNA and nuclear receptors. Specifically, we examine how these molecular players influence the chemoresistance mechanism. By exploring the interplay between these factors and gene expression regulation, this review seeks to provide a comprehensive mechanism driving chemoresistance in OC.
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Affiliation(s)
| | - Pankaj Kumar Giri
- Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi 110068, India
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Xin Z, Wen X, Zhou M, Lin H, Liu J. Identification of molecular characteristics of FUT8 and alteration of core fucosylation in kidney renal clear cell cancer. Aging (Albany NY) 2024; 16:2299-2319. [PMID: 38277230 PMCID: PMC10911337 DOI: 10.18632/aging.205482] [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: 09/13/2023] [Accepted: 12/04/2023] [Indexed: 01/28/2024]
Abstract
BACKGROUND Kidney renal clear cell cancer (KIRC) is a type of urological cancer that occurs worldwide. Core fucosylation (CF), as the most common post-translational modification, is involved in the tumorigenesis. METHODS The alterations of CF-related genes were summarized in pan-cancer. The "ConsensusClusterPlus" package was utilized to identify two CF-related KIRC subtypes. The "ssgsea" function was chosen to estimate the CF score, signaling pathways and cell deaths. Multiple algorithms were applied to assess immune responses. The "oncoPredict" was utilized to estimate the drug sensitivity. The IHC and subgroup analysis was performed to reveal the molecular features of FUT8. Single-cell RNA sequencing (scRNA-seq) data were scrutinized to evaluate the CF state. RESULTS In pan-cancer, there was a noticeable alteration in the expression of CF-related genes. In KIRC, two CF-related subtypes (i.e., C1, C2) were obtained. In comparison to C2, C1 exhibited a higher CF score and correlated with poorer overall survival. Additionally, the TME of C2 demonstrated increased activity in neutrophils, macrophages, myeloid dendritic cells, and B cells, alongside a higher presence of silent mast cells, NK cells, and endothelial cells. Compared to normal samples, higher expression of FUT8 is observed in KIRC. The mutation of SETD2 was more frequent in low-FUT8 samples while the mutation of DNAH9 was more frequent in high-FUT8 samples. scRNA-seq analyses revealed that the CF score was predominantly higher in endothelial cells and fibroblast cells. CONCLUSIONS Two CF-related subtypes with distinct prognosis and TME were identified in KIRC. FUT8 exhibited elevated expression in KIRC samples.
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Affiliation(s)
- Zhu Xin
- Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Key Laboratory of Kidney Disease of Liaoning Province, The Center for the Transformation Medicine of Kidney Disease of Liaoning Province, Dalian, China
- Liaoning Laboratory of Cancer Genomics and Epigenomics, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Xinyu Wen
- Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Key Laboratory of Kidney Disease of Liaoning Province, The Center for the Transformation Medicine of Kidney Disease of Liaoning Province, Dalian, China
| | - Mengying Zhou
- Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Key Laboratory of Kidney Disease of Liaoning Province, The Center for the Transformation Medicine of Kidney Disease of Liaoning Province, Dalian, China
| | - Hongli Lin
- Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Key Laboratory of Kidney Disease of Liaoning Province, The Center for the Transformation Medicine of Kidney Disease of Liaoning Province, Dalian, China
| | - Jia Liu
- Liaoning Laboratory of Cancer Genomics and Epigenomics, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
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Shi M, Nan XR, Liu BQ. The Multifaceted Role of FUT8 in Tumorigenesis: From Pathways to Potential Clinical Applications. Int J Mol Sci 2024; 25:1068. [PMID: 38256141 PMCID: PMC10815953 DOI: 10.3390/ijms25021068] [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: 01/07/2024] [Accepted: 01/13/2024] [Indexed: 01/24/2024] Open
Abstract
FUT8, the sole glycosyltransferase responsible for N-glycan core fucosylation, plays a crucial role in tumorigenesis and development. Aberrant FUT8 expression disrupts the function of critical cellular components and triggers the abnormality of tumor signaling pathways, leading to malignant transformations such as proliferation, invasion, metastasis, and immunosuppression. The association between FUT8 and unfavorable outcomes in various tumors underscores its potential as a valuable diagnostic marker. Given the remarkable variation in biological functions and regulatory mechanisms of FUT8 across different tumor types, gaining a comprehensive understanding of its complexity is imperative. Here, we review how FUT8 plays roles in tumorigenesis and development, and how this outcome could be utilized to develop potential clinical therapies for tumors.
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Affiliation(s)
| | | | - Bao-Qin Liu
- Department of Biochemistry & Molecular Biology, School of Life Sciences, China Medical University, Shenyang 110122, China; (M.S.); (X.-R.N.)
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11
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Zhang NZ, Zhao LF, Zhang Q, Fang H, Song WL, Li WZ, Ge YS, Gao P. Core fucosylation and its roles in gastrointestinal glycoimmunology. World J Gastrointest Oncol 2023; 15:1119-1134. [PMID: 37546555 PMCID: PMC10401475 DOI: 10.4251/wjgo.v15.i7.1119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/28/2023] [Accepted: 05/08/2023] [Indexed: 07/12/2023] Open
Abstract
Glycosylation is a common post-translational modification in eukaryotic cells. It is involved in the production of many biologically active glycoproteins and the regulation of protein structure and function. Core fucosylation plays a vital role in the immune response. Most immune system molecules are core fucosylated glycoproteins such as complements, cluster differentiation antigens, immunoglobulins, cytokines, major histocompatibility complex molecules, adhesion molecules, and immune molecule synthesis-related transcription factors. These core fucosylated glycoproteins play important roles in antigen recognition and clearance, cell adhesion, lymphocyte activation, apoptosis, signal transduction, and endocytosis. Core fucosylation is dominated by fucosyltransferase 8 (Fut8), which catalyzes the addition of α-1,6-fucose to the innermost GlcNAc residue of N-glycans. Fut8 is involved in humoral, cellular, and mucosal immunity. Tumor immunology is associated with aberrant core fucosylation. Here, we summarize the roles and potential modulatory mechanisms of Fut8 in various immune processes of the gastrointestinal system.
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Affiliation(s)
- Nian-Zhu Zhang
- Clinical Laboratory, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Li-Fen Zhao
- Clinical Laboratory, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Qian Zhang
- Department of Cell Therapy, Shanghai Tianze Yuntai Biomedical Co., Ltd., Shanghai 200100, China
| | - Hui Fang
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba 305-0005, Ibaraki, Japan
| | - Wan-Li Song
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Zhe Li
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu-Song Ge
- Department of Neurology, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Peng Gao
- Clinical Laboratory, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
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12
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Xu X, Wu Y, Jia G, Zhu Q, Li D, Xie K. A signature based on glycosyltransferase genes provides a promising tool for the prediction of prognosis and immunotherapy responsiveness in ovarian cancer. J Ovarian Res 2023; 16:5. [PMID: 36611197 PMCID: PMC9826597 DOI: 10.1186/s13048-022-01088-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 12/22/2022] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Ovarian cancer (OC) is the most fatal gynaecological malignancy and has a poor prognosis. Glycosylation, the biosynthetic process that depends on specific glycosyltransferases (GTs), has recently attracted increasing importance due to the vital role it plays in cancer. In this study, we aimed to determine whether OC patients could be stratified by glycosyltransferase gene profiles to better predict the prognosis and efficiency of immune checkpoint blockade therapies (ICBs). METHODS We retrieved transcriptome data across 420 OC and 88 normal tissue samples using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, respectively. An external validation dataset containing 185 OC samples was downloaded from the Gene Expression Omnibus (GEO) database. Knockdown and pathway prediction of B4GALT5 were conducted to investigate the function and mechanism of B4GALT5 in OC proliferation, migration and invasion. RESULTS A total of 50 differentially expressed GT genes were identified between OC and normal ovarian tissues. Two clusters were stratified by operating consensus clustering, but no significant prognostic value was observed. By applying the least absolute shrinkage and selection operator (LASSO) Cox regression method, a 6-gene signature was built that classified OC patients in the TCGA cohort into a low- or high-risk group. Patients with high scores had a worse prognosis than those with low scores. This risk signature was further validated in an external GEO dataset. Furthermore, the risk score was an independent risk predictor, and a nomogram was created to improve the accuracy of prognostic classification. Notably, the low-risk OC patients exhibited a higher degree of antitumor immune cell infiltration and a superior response to ICBs. B4GALT5, one of six hub genes, was identified as a regulator of proliferation, migration and invasion in OC. CONCLUSION Taken together, we established a reliable GT-gene-based signature to predict prognosis, immune status and identify OC patients who would benefit from ICBs. GT genes might be a promising biomarker for OC progression and a potential therapeutic target for OC.
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Affiliation(s)
- Xuyao Xu
- grid.459791.70000 0004 1757 7869Department of Gynecology, Nanjing Maternity and Child Health Care Hospital, Women’s Hospital of Nanjing Medical University, Nanjing, 210004 China
| | - Yue Wu
- grid.459791.70000 0004 1757 7869Department of Gynecology, Nanjing Maternity and Child Health Care Hospital, Women’s Hospital of Nanjing Medical University, Nanjing, 210004 China
| | - Genmei Jia
- grid.459791.70000 0004 1757 7869Department of Women Health Care, Nanjing Maternity and Child Health Care Hospital, Women’s Hospital of Nanjing Medical University, Nanjing, 210004 China
| | - Qiaoying Zhu
- grid.459791.70000 0004 1757 7869Department of Gynecology, Nanjing Maternity and Child Health Care Hospital, Women’s Hospital of Nanjing Medical University, Nanjing, 210004 China
| | - Dake Li
- grid.459791.70000 0004 1757 7869Department of Gynecology, Nanjing Maternity and Child Health Care Hospital, Women’s Hospital of Nanjing Medical University, Nanjing, 210004 China
| | - Kaipeng Xie
- grid.459791.70000 0004 1757 7869Department of Women Health Care, Nanjing Maternity and Child Health Care Hospital, Women’s Hospital of Nanjing Medical University, Nanjing, 210004 China ,grid.459791.70000 0004 1757 7869Department of Public Health, Nanjing Maternity and Child Health Care Hospital, Women’s Hospital of Nanjing Medical University, Nanjing, 210004 China
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13
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Lv Y, Zhang Z, Tian S, Wang W, Li H. Therapeutic potential of fucosyltransferases in cancer and recent development of targeted inhibitors. Drug Discov Today 2023; 28:103394. [PMID: 36223858 DOI: 10.1016/j.drudis.2022.103394] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 09/05/2022] [Accepted: 10/04/2022] [Indexed: 11/05/2022]
Abstract
Fucosyltransferases (FUTs) have significant roles in various pathophysiological events. Their high expression is a signature of malignant cell transformation, contributing to many abnormal events during cancer development, such as uncontrolled cell proliferation, tumor cell invasion, angiogenesis, metastasis, immune evasion, and therapy resistance. Therefore, FUTs have evolved as an attractive therapeutic target for treating solid cancers, and many substrate analogs have been discovered with potential as FUT inhibitors for cancer therapy. Meanwhile, the development of FUT protein structures represents a significant advance in the design of FUT inhibitors with nonsubstrate structures. In this review, we summarize the role of FUTs in cancers, the resolved protein crystal structures and progress in the development of FUT inhibitors as cancer therapeutics.
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Affiliation(s)
- Yixin Lv
- College of Pharmaceutical Sciences, Soochow University, Suzhou 215006, Jiangsu, China
| | - Zhoudong Zhang
- College of Pharmaceutical Sciences, Soochow University, Suzhou 215006, Jiangsu, China
| | - Sheng Tian
- College of Pharmaceutical Sciences, Soochow University, Suzhou 215006, Jiangsu, China
| | - Weipeng Wang
- College of Pharmaceutical Sciences, Soochow University, Suzhou 215006, Jiangsu, China.
| | - Huanqiu Li
- College of Pharmaceutical Sciences, Soochow University, Suzhou 215006, Jiangsu, China.
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14
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Saburi A, Kahrizi MS, Naghsh N, Etemadi H, İlhan A, Adili A, Ghoreishizadeh S, Tamjidifar R, Akbari M, Ercan G. A comprehensive survey into the role of microRNAs in ovarian cancer chemoresistance; an updated overview. J Ovarian Res 2022; 15:81. [PMID: 35799305 PMCID: PMC9264529 DOI: 10.1186/s13048-022-01012-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 06/23/2022] [Indexed: 11/30/2022] Open
Abstract
Ovarian cancer (OC), a frequent malignant tumor that affects women, is one of the leading causes of cancer-related death in this group of individuals. For the treatment of ovarian cancer, systemic chemotherapy with platinum-based drugs or taxanes is the first-line option. However, drug resistance developed over time during chemotherapy medications worsens the situation. Since uncertainty exists for the mechanism of chemotherapy resistance in ovarian cancer, there is a need to investigate and overcome this problem. miRNAs are engaged in various signaling pathways that contribute to the chemotherapeutic resistance of ovarian cancer. In the current study, we have tried to shed light on the mechanisms by which microRNAs contribute to the drug resistance of ovarian cancer and the use of some microRNAs to combat this chemoresistance, leading to the worse outcome of ovarian cancer patients treated with systemic chemotherapeutics.
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Affiliation(s)
- Ahmad Saburi
- Department of Biology, Faculty of Basic Sciences, Gonbad Kavous University, Gonbad Kavous, Iran
| | | | - Navid Naghsh
- Department of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Hasti Etemadi
- Department of Biotechnology, Rajiv Gandhi Institute of IT and Biotechnology, Bharati Vidyapeeth University, Pune, India
| | - Ahmet İlhan
- Department of Medical Biochemistry, Faculty of Medicine, Cukurova University, Adana, Turkey
| | - Ali Adili
- Senior Adult Oncology Department, Moffitt Cancer Center, University of South Florida, Tampa, Florida USA
- Department of Oncology, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Rozita Tamjidifar
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Biochemistry, Faculty of Medicine, Ege University, Izmir, 35100 Turkey
| | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Gülinnaz Ercan
- Department of Medical Biochemistry, Faculty of Medicine, Ege University, Izmir, 35100 Turkey
- Department of Stem Cell, Institute of Health Sciences, Ege University, Izmir, 35100 Turkey
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15
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Su Y, Zhang X, Li S, Xie W, Guo J. Emerging roles of the copper-CTR1 axis in tumorigenesis. Mol Cancer Res 2022; 20:1339-1353. [PMID: 35604085 DOI: 10.1158/1541-7786.mcr-22-0056] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/09/2022] [Accepted: 05/17/2022] [Indexed: 11/16/2022]
Abstract
Physiological roles of copper in metabolic homeostasis have been well established, however, whether and how copper is dysregulated in tumors and contributes to tumorigenesis are not recapitulated. Here, we comprehensively summarize the potential origins of copper accumulation in diseases especially in cancers by dysregulating copper transporter 1 (CTR1) or ATPase copper transporting alpha/beta (ATP7A/B) and further demonstrate the underlying mechanism of copper contributing to tumorigenesis. Specifically, in addition to modulating reactive oxygen species (ROS), angiogenesis, immune response, and metabolic homeostasis, copper recently has drawn more attention by directly binding to oncoproteins such as MEK, ULK, Memo, and PDK1 to activate distinct oncogenic signals and account for tumorigenesis. In the end, we disclose the emerging applications of copper in cancer diagnosis and highlight the promising strategies to target the copper-CTR1 axis for cancer therapies.
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Affiliation(s)
- Yaqing Su
- First Affiliated Hospital of Sun Yat-sen University, guangzhou, guangdong, China
| | - Xiaomei Zhang
- First Affiliated Hospital of Sun Yat-sen University, China
| | - Shaoqiang Li
- The First Affiliatd Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wei Xie
- First Affiliated Hospital of Sun Yat-sen University, China
| | - Jianping Guo
- First Affiliated Hospital of Sun Yat-sen University, guangzhou, guangdong, China
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16
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Sun Y, Li X, Wang T, Li W. Core Fucosylation Regulates the Function of Pre-BCR, BCR and IgG in Humoral Immunity. Front Immunol 2022; 13:844427. [PMID: 35401499 PMCID: PMC8990897 DOI: 10.3389/fimmu.2022.844427] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 02/25/2022] [Indexed: 11/20/2022] Open
Abstract
Most of the membrane molecules involved in immune response are glycosylated. N-glycans linked to asparagine (Asn) of immune molecules contribute to the protein conformation, surface expression, stability, and antigenicity. Core fucosylation catalyzed by core fucosyltransferase (FUT8) is the most common post-translational modification. Core fucosylation is essential for evoking a proper immune response, which this review aims to communicate. First, FUT8 deficiency suppressed the interaction between μHC and λ5 during pre-BCR assembly is given. Second, we described the effects of core fucosylation in B cell signal transduction via BCR. Third, we investigated the role of core fucosylation in the interaction between helper T (TH) cells and B cells. Finally, we showed the role of FUT8 on the biological function of IgG. In this review, we discussed recent insights into the sites where core fucosylation is critical for humoral immune responses.
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Affiliation(s)
- Yuhan Sun
- College of Basic Medical Science, Dalian Medical University, Dalian, China
- Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, Sendai, Japan
| | - Xueying Li
- Research Institute for Microbial Diseases and World Premier International Immunology Frontier Research Center, Osaka University, Suita, Japan
| | - Tiantong Wang
- College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Wenzhe Li
- College of Basic Medical Science, Dalian Medical University, Dalian, China
- *Correspondence: Wenzhe Li,
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17
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Therapeutic strategies to overcome cisplatin resistance in ovarian cancer. Eur J Med Chem 2022; 232:114205. [DOI: 10.1016/j.ejmech.2022.114205] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 02/12/2022] [Accepted: 02/14/2022] [Indexed: 12/15/2022]
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18
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Hires M, Jane E, Kalavska K, Chovanec M, Mego M, Kasak P, Bertok T, Tkac J. Glycan signatures for the identification of cisplatin‐resistant testicular cancer cell lines: Specific glycoprofiling of human chorionic gonadotropin (hCG). Cancer Med 2022; 11:968-982. [PMID: 35044085 PMCID: PMC8855906 DOI: 10.1002/cam4.4515] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/03/2021] [Accepted: 11/21/2021] [Indexed: 12/14/2022] Open
Abstract
Background Testicular cancer (TC) is the most frequent type of cancer among young men aged between 15 and 34 years. TC is treated using cisplatin, but 3%–5% of TC patients fail to respond to cisplatin, with a very bad to fatal prognosis. Accordingly, it is most important to quickly and readily identify those TC patients who are resistant to cisplatin treatment. Methods This study seeks to investigate changes in the glycosylation associated with cisplatin resistance to TC cell lines. Results A specific glycoprofiling of human chorionic gonadotropin (hCG) was analysed in three TC cell lines and one cell line of female origin. A typical calibration curve for hCG glycoprofiling showed a dynamic range up to 50 ng/ml, with a limit of detection of 0.3 ng/ml and assay reproducibility represented by relative standard deviation of 3.0%. Changes in the glycan signatures on hCG were analysed in cisplatin‐sensitive cell lines and in their cisplatin‐resistant sub‐lines using an enzyme‐linked lectin assay (ELLA) protocol. An immobilised antibody was applied to a selective capture of hCG from a cytoplasmic fraction of cell lysates with final incubation using a lectin from a panel of 17 lectins. Conclusion The results suggest that one particular lectin Dolichos biflorus agglutinin (DBA) can selectively discriminate sensitive TC cell lines from resistant TC cell lines. Moreover, there are additional lectins which can provide useful information about the strength of cisplatin resistance.
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Affiliation(s)
- Michal Hires
- Institute of Chemistry Slovak Academy of Sciences Bratislava Slovakia
| | - Eduard Jane
- Institute of Chemistry Slovak Academy of Sciences Bratislava Slovakia
| | - Katarina Kalavska
- Translational Research Unit Faculty of Medicine Comenius University and National Cancer Institute Bratislava Slovakia
| | - Michal Chovanec
- 2nd Department of Oncology Faculty of Medicine Comenius University and National Cancer Institute Bratislava Slovakia
| | - Michal Mego
- Translational Research Unit Faculty of Medicine Comenius University and National Cancer Institute Bratislava Slovakia
- 2nd Department of Oncology Faculty of Medicine Comenius University and National Cancer Institute Bratislava Slovakia
| | - Peter Kasak
- Center for Advanced Materials Qatar University Doha Qatar
| | - Tomas Bertok
- Institute of Chemistry Slovak Academy of Sciences Bratislava Slovakia
| | - Jan Tkac
- Institute of Chemistry Slovak Academy of Sciences Bratislava Slovakia
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19
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Li G, Gong J, Cao S, Wu Z, Cheng D, Zhu J, Huang X, Tang J, Yuan Y, Cai W, Zhang H. The Non-Coding RNAs Inducing Drug Resistance in Ovarian Cancer: A New Perspective for Understanding Drug Resistance. Front Oncol 2021; 11:742149. [PMID: 34660304 PMCID: PMC8514763 DOI: 10.3389/fonc.2021.742149] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 09/10/2021] [Indexed: 12/30/2022] Open
Abstract
Ovarian cancer, a common malignant tumor, is one of the primary causes of cancer-related deaths in women. Systemic chemotherapy with platinum-based compounds or taxanes is the first-line treatment for ovarian cancer. However, resistance to these chemotherapeutic drugs worsens the prognosis. The underlying mechanism of chemotherapeutic resistance in ovarian cancer remains unclear. Non-coding RNAs, including long non-coding RNAs, microRNAs, and circular RNAs, have been implicated in the development of drug resistance. Abnormally expressed non-coding RNAs can promote ovarian cancer resistance by inducing apoptosis inhibition, protective autophagy, abnormal tumor cell proliferation, epithelial-mesenchymal transition, abnormal glycolysis, drug efflux, and cancer cell stemness. This review summarizes the role of non-coding RNAs in the development of chemotherapeutic resistance in ovarian cancer, including their mechanisms, targets, and potential signaling pathways. This will facilitate the development of novel chemotherapeutic agents that can target these non-coding RNAs and improve ovarian cancer treatment.
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Affiliation(s)
- Gaofeng Li
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
| | - Jun Gong
- Department of Abdominal and Pelvic Medical Oncology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, China
| | - Shulong Cao
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
| | - Zhaoyang Wu
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
| | - Dong Cheng
- Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Zhu
- Hubei Enshi College, Enshi, China
| | - Xuqun Huang
- Department of Thoracic Medical Oncology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, China
| | - Jingyi Tang
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
| | - Yuning Yuan
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
| | - Wenqi Cai
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
| | - Haiyuan Zhang
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, China
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20
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Wu G, Peng H, Tang M, Yang M, Wang J, Hu Y, Li Z, Li J, Li Z, Song L. ZNF711 down-regulation promotes CISPLATIN resistance in epithelial ovarian cancer via interacting with JHDM2A and suppressing SLC31A1 expression. EBioMedicine 2021; 71:103558. [PMID: 34521054 PMCID: PMC8441092 DOI: 10.1016/j.ebiom.2021.103558] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 08/10/2021] [Accepted: 08/13/2021] [Indexed: 01/07/2023] Open
Abstract
Background Resistance to platinum-based chemotherapy is a major cause of therapeutic failure during the treatment of epithelial ovarian cancer (EOC) patients. Our study aims to elucidate the molecular mechanisms by which ZNF711 down regulation promotes CISPLATIN resistance in EOC. Methods ZNF711 expression in 150 EOC specimens was examined using immunohistochemistry. ZNF711 expression and the survival of EOC patients were assessed with a Kaplan-Meier analysis. The effects of ZNF711 expression on CDDP resistance were studied by IC50, Annexin V, and colony formation in vitro, and in an in vivo intra-peritoneal tumor model. The molecular mechanism was determined using a luciferase reporter assay, ChIP assay, CAPTURE approach, and co-IP assay. Findings ZNF711 down-regulation exerts a great impact on CDDP resistance for EOC patients by suppressing SLC31A1 and inhibiting CDDP influx. ZNF711 down-regulation promoted, while ZNF711 overexpression drastically inhibited CDDP resistance, both in vivo and in vitro. Mechanistically, the histone demethylase JHDM2A was recruited to the SLC31A1 promoter by ZNF711 and decreased the H3K9me2 level, resulting in the activation of SLC31A1 transcription and enhancement of CDDP uptake. Importantly, co-treatment with the histone methylation inhibitor, BIX-01294, increased the therapeutic efficacy of CDDP treatment in ZNF711-suppressed EOC cells. Interpretation These findings both verified the clinical importance of ZNF711 in CDDP resistance and provide novel therapeutic regimens for EOC treatment. Funding This work was supported by the Natural Science Foundation of China; Guangzhou Science and Technology Plan Projects; Natural Science Foundation of Guangdong Province; The Fundamental Research Funds for the Central Universities; and China Postdoctoral Science Foundation.
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Affiliation(s)
- Geyan Wu
- State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Hu Peng
- Department of Gynecological Oncology, Hubei Cancer Hospital, Wuhan 430071, China
| | - Miaoling Tang
- State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Meisongzhu Yang
- Department of biochemistry, Zhongshan school of medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Jun Wang
- Department of Gynecologic Oncology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Tumor Hospital), Kunming 650118, China
| | - Yameng Hu
- Department of biochemistry, Zhongshan school of medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Ziwen Li
- Department of biochemistry, Zhongshan school of medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Jun Li
- Department of biochemistry, Zhongshan school of medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Zheng Li
- Department of Gynecologic Oncology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Tumor Hospital), Kunming 650118, China.
| | - Libing Song
- State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
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21
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Liao C, An J, Yi S, Tan Z, Wang H, Li H, Guan X, Liu J, Wang Q. FUT8 and Protein Core Fucosylation in Tumours: From Diagnosis to Treatment. J Cancer 2021; 12:4109-4120. [PMID: 34093814 PMCID: PMC8176256 DOI: 10.7150/jca.58268] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 04/27/2021] [Indexed: 02/07/2023] Open
Abstract
Glycosylation changes are key molecular events in tumorigenesis, progression and glycosyltransferases play a vital role in the this process. FUT8 belongs to the fucosyltransferase family and is the key enzyme involved in N-glycan core fucosylation. FUT8 and/or core fucosylated proteins are frequently upregulated in liver, lung, colorectal, pancreas, prostate,breast, oral cavity, oesophagus, and thyroid tumours, diffuse large B-cell lymphoma, ependymoma, medulloblastoma and glioblastoma multiforme and downregulated in gastric cancer. They can be used as markers of cancer diagnosis, occurrence, progression and prognosis. Core fucosylated EGFR, TGFBR, E-cadherin, PD1/PD-L1 and α3β1 integrin are potential targets for tumour therapy. In addition, IGg1 antibody defucosylation can improve antibody affinity, which is another aspect of FUT8 that could be applied to tumour therapy.
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Affiliation(s)
- Chengcheng Liao
- Special Key Laboratory of Oral Disease Research, Higher Education Institution in Guizhou Province, School of Stomatology, Zunyi Medical University, Zunyi 563006, China
| | - Jiaxing An
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Suqin Yi
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Zhangxue Tan
- Special Key Laboratory of Oral Disease Research, Higher Education Institution in Guizhou Province, School of Stomatology, Zunyi Medical University, Zunyi 563006, China
| | - Hui Wang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Hao Li
- Special Key Laboratory of Oral Disease Research, Higher Education Institution in Guizhou Province, School of Stomatology, Zunyi Medical University, Zunyi 563006, China
| | - Xiaoyan Guan
- Department of Orthodontics II, Hospital of Stomatology, Zunyi Medical University, Zunyi 563000, China
| | - Jianguo Liu
- Special Key Laboratory of Oral Disease Research, Higher Education Institution in Guizhou Province, School of Stomatology, Zunyi Medical University, Zunyi 563006, China
| | - Qian Wang
- Special Key Laboratory of Oral Disease Research, Higher Education Institution in Guizhou Province, School of Stomatology, Zunyi Medical University, Zunyi 563006, China.,Microbial Resources and Drug Development Key Laboratory of Guizhou Tertiary Institution, Life Sciences Institute, Zunyi Medical University, Zunyi 563006, China
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22
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Ohkawa Y, Harada Y, Taniguchi N. Keratan sulfate-based glycomimetics using Langerin as a target for COPD: lessons from studies on Fut8 and core fucose. Biochem Soc Trans 2021; 49:441-453. [PMID: 33616615 PMCID: PMC7924997 DOI: 10.1042/bst20200780] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/14/2021] [Accepted: 01/29/2021] [Indexed: 12/19/2022]
Abstract
Glycosylation represents one of the most abundant posttranslational modification of proteins. Glycosylation products are diverse and are regulated by the cooperative action of various glycosyltransferases, glycosidases, substrates thereof: nucleoside sugars and their transporters, and chaperons. In this article, we focus on a glycosyltransferase, α1,6-fucosyltransferase (Fut8) and its product, the core fucose structure on N-glycans, and summarize the potential protective functions of this structure against emphysema and chronic obstructive pulmonary disease (COPD). Studies of FUT8 and its enzymatic product, core fucose, are becoming an emerging area of interest in various fields of research including inflammation, cancer and therapeutics. This article discusses what we can learn from studies of Fut8 and core fucose by using knockout mice or in vitro studies that were conducted by our group as well as other groups. We also include a discussion of the potential protective functions of the keratan sulfate (KS) disaccharide, namely L4, against emphysema and COPD as a glycomimetic. Glycomimetics using glycan analogs is one of the more promising therapeutics that compensate for the usual therapeutic strategy that involves targeting the genome and the proteome. These typical glycans using KS derivatives as glycomimetics, will likely become a clue to the development of novel and effective therapeutic strategies.
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MESH Headings
- Animals
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Antigens, Surface/genetics
- Antigens, Surface/metabolism
- Antigens, Surface/physiology
- Biomimetic Materials/chemistry
- Biomimetic Materials/therapeutic use
- Fucose/metabolism
- Fucosyltransferases/physiology
- Glycosylation
- Humans
- Keratan Sulfate/chemistry
- Lectins, C-Type/antagonists & inhibitors
- Lectins, C-Type/genetics
- Lectins, C-Type/metabolism
- Lectins, C-Type/physiology
- Mannose-Binding Lectins/antagonists & inhibitors
- Mannose-Binding Lectins/genetics
- Mannose-Binding Lectins/metabolism
- Mannose-Binding Lectins/physiology
- Mice
- Mice, Knockout
- Molecular Targeted Therapy/methods
- Polysaccharides/chemistry
- Polysaccharides/metabolism
- Pulmonary Disease, Chronic Obstructive/drug therapy
- Pulmonary Disease, Chronic Obstructive/genetics
- Pulmonary Disease, Chronic Obstructive/metabolism
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Affiliation(s)
- Yuki Ohkawa
- Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka 541-8567, Japan
| | - Yoichiro Harada
- Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka 541-8567, Japan
| | - Naoyuki Taniguchi
- Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka 541-8567, Japan
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23
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Bastian K, Scott E, Elliott DJ, Munkley J. FUT8 Alpha-(1,6)-Fucosyltransferase in Cancer. Int J Mol Sci 2021; 22:E455. [PMID: 33466384 PMCID: PMC7795606 DOI: 10.3390/ijms22010455] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 12/21/2020] [Accepted: 12/24/2020] [Indexed: 12/15/2022] Open
Abstract
Aberrant glycosylation is a universal feature of cancer cells that can impact all steps in tumour progression from malignant transformation to metastasis and immune evasion. One key change in tumour glycosylation is altered core fucosylation. Core fucosylation is driven by fucosyltransferase 8 (FUT8), which catalyses the addition of α1,6-fucose to the innermost GlcNAc residue of N-glycans. FUT8 is frequently upregulated in cancer, and plays a critical role in immune evasion, antibody-dependent cellular cytotoxicity (ADCC), and the regulation of TGF-β, EGF, α3β1 integrin and E-Cadherin. Here, we summarise the role of FUT8 in various cancers (including lung, liver, colorectal, ovarian, prostate, breast, melanoma, thyroid, and pancreatic), discuss the potential mechanisms involved, and outline opportunities to exploit FUT8 as a critical factor in cancer therapeutics in the future.
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Affiliation(s)
- Kayla Bastian
- Institute of Biosciences, Newcastle University, Newcastle Upon Tyne NE1 3BZ, UK; (E.S.); (D.J.E.); (J.M.)
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24
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Taniguchi N, Ohkawa Y, Maeda K, Harada Y, Nagae M, Kizuka Y, Ihara H, Ikeda Y. True significance of N-acetylglucosaminyltransferases GnT-III, V and α1,6 fucosyltransferase in epithelial-mesenchymal transition and cancer. Mol Aspects Med 2020; 79:100905. [PMID: 33010941 DOI: 10.1016/j.mam.2020.100905] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 09/02/2020] [Indexed: 12/13/2022]
Abstract
It is well known that numerous cancer-related changes occur in glycans that are attached to glycoproteins, glycolipids and proteoglycans on the cell surface and these changes in structure and the expression of the glycans are largely regulated by glycosyl-transferases, glycosidases, nucleotide sugars and their related genes. Such structural changes in glycans on cell surface proteins may accelerate the progression, invasion and metastasis of cancer cells. Among the over 200 known glycosyltransferases and related genes, β 1,6 N-acetylglucosaminyltransferase V (GnT-V) (the MGAT5 gene) and α 1,6 fucosyltransferase (FUT8) (the FUT8 gene) are representative enzymes in this respect because changes in glycans caused by these genes appear to be related to cancer metastasis and invasion in vitro as well as in vivo, and a number of reports on these genes in related to epithelial-mesenchymal transition (EMT) have also appeared. Another enzyme, one of the N-glycan branching enzymes, β1,4 N-acetylglucosaminyltransferase III (GnT-III) (the MGAT3 gene) has been reported to suppress EMT. However, there are intermediate states between EMT and mesenchymal-epithelial transition (MET) and some of these genes have been implicated in both EMT and MET and are also probably in an intermediate state. Therefore, it would be difficult to clearly define which specific glycosyltransferase is involved in EMT or MET or an intermediate state. The significance of EMT and N-glycan branching glycosyltransferases needs to be reconsidered and the inhibition of their corresponding genes would also be desirable in therapeutics. This review mainly focuses on GnT-III, GnT-V and FUT8, major players as N-glycan branching enzymes in cancer in relation to EMT programs, and also discusses the catalytic mechanisms of GnT-V and FUT8 whose crystal structures have now been obtained.
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Affiliation(s)
- Naoyuki Taniguchi
- Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, Osaka, Japan.
| | - Yuki Ohkawa
- Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, Osaka, Japan.
| | - Kento Maeda
- Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, Osaka, Japan.
| | - Yoichiro Harada
- Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, Osaka, Japan.
| | - Masamichi Nagae
- Department of Molecular Immunology, RIMD, Osaka University, Osaka, Japan.
| | - Yasuhiko Kizuka
- Glyco-biochemistry Laboratory, G-Chain, Gifu University, Gifu, Japan.
| | - Hideyuki Ihara
- Division of Molecular Cell Biology, Department of Biomolecular Sciences, Saga University Faculty of Medicine, Saga, Japan.
| | - Yoshitaka Ikeda
- Division of Molecular Cell Biology, Department of Biomolecular Sciences, Saga University Faculty of Medicine, Saga, Japan.
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25
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Montazeri V, Ghahremani MH, Montazeri H, Hasanzad M, Safavi DM, Ayati M, Chehrazi M, Arefi Moghaddam B, Ostad SN. A Preliminary Study of NER and MMR Pathways Involved in Chemotherapy Response in Bladder Transitional Cell Carcinoma: Impact on progression-free survival. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2020; 19:355-365. [PMID: 32922493 PMCID: PMC7462481 DOI: 10.22037/ijpr.2020.112646.13878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
One of the main genotoxic drugs used in bladder cancer chemotherapy is cisplatin. While it is applied in most types of cancers, resistance to cisplatin is wildly common. In order to overcome drug resistance, it is necessary to determine a predictive marker. This study was conducted to provide basic data for selecting and designing a gene profile for further cohort and RCT studies in the future to improve response to treatment in bladder cancer. The expression levels of ERCC1, MLH1, MSH2, and CTR1 mRNA were determined in the tumor tissue using real-time q-PCR. Progression-free survival (PFS) was analyzed in term of the level of genes expression. The results revealed that the level of ERCC1 mRNA expression was higher in the recurrence (R) group compared to the no recurrence (NR) group. Moreover, the PFS time was increased in the patients with an ERCC1 expression level of below 1.57. The level of MLH1 and MSH2 mRNA expression was lower in the R group compared to the NR group; therefore, PFS time was increased in the patients with MLH1 and MSH2 gene expression levels above the cutoff point. While the level of CTR1 mRNA expression was higher in the R group versus the NR group, the PFS time was longer in the patients with CTR1 expression levels of below 1.265 compared to the patients with high levels of CTR1 expression. It can be concluded that the level of ERCC1, MLH1, MSH2, and CTR1 mRNA expression may be associated with PFS time as possible therapeutic targets for decreasing cisplatin resistance.
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Affiliation(s)
- Vahideh Montazeri
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Ghahremani
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Montazeri
- Department of Pharmaceutical Biotechnology, School of Pharmacy, International Campus, Iran University of Medical Sciences, Tehran, Iran
| | - Mandana Hasanzad
- Medical Genomics Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - D Majid Safavi
- Urology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Ayati
- Uro-Oncology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Chehrazi
- Department of Biostatistics and Epidemiology, School of Public Health, Babol University of Medical Sciences, Babol, Iran
| | | | - Seyed Nasser Ostad
- Toxicology and Poisoning Research Centre, Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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26
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Zhang N, Li M, Xu X, Zhang Y, Liu Y, Zhao M, Li P, Chen J, Fukuda T, Gu J, Jin X, Li W. Loss of core fucosylation enhances the anticancer activity of cytotoxic T lymphocytes by increasing PD-1 degradation. Eur J Immunol 2020; 50:1820-1833. [PMID: 32460355 DOI: 10.1002/eji.202048543] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 04/24/2020] [Accepted: 05/25/2020] [Indexed: 12/13/2022]
Abstract
As an immune checkpoint, programmed cell death 1 (PD-1) and its ligand (PD-L1) pathway plays a crucial role in CD8+ cytotoxic T lymphocytes (CTL) activation and provides antitumor responses. The N-glycans of PD-1 and PD-L1 are highly core fucosylated, which are solely catalyzed by the core fucosyltransferase (Fut8). However, the precise biological mechanisms underlying effects of core fucosylation of PD-1 and PD-L1 on CTL activation have not been fully understood. In this study, we found that core fucosylation was significantly upregulated in lung adenocarcinoma. Compared to those of Fut8+/+ OT-I mice, the lung adenocarcinoma formation induced by urethane was markedly reduced in Fut8-/- OT-I mice. De-core fucosylation of PD-1 compromised its expression on Fut8-/- CTL, resulted in enhanced Fut8-/- CTL activation and cytotoxicity, leading to more efficient tumor eradication. Indeed, loss of core fucosylation significantly enhanced the PD-1 ubiquitination and in turn led to the degradation of PD-1 in the proteasome. Our current work indicates that inhibition of core fucosylation is a unique strategy to reduce PD-1 expression for the antilung adenocarcinoma immune therapy in the future.
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Affiliation(s)
- Nianzhu Zhang
- College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
| | - Ming Li
- College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
| | - Xing Xu
- Tianjin Medical University Cancer Institute and Hospital. National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin. Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yingshu Zhang
- College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
| | - Yancheng Liu
- Tianjin Medical University Cancer Institute and Hospital. National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin. Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Meng Zhao
- Tianjin Medical University Cancer Institute and Hospital. National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin. Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Peng Li
- Tianjin Medical University Cancer Institute and Hospital. National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin. Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jun Chen
- Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Tomohiko Fukuda
- Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan
| | - Jianguo Gu
- Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan
| | - Xun Jin
- Tianjin Medical University Cancer Institute and Hospital. National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin. Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Wenzhe Li
- College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
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27
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Mo X, Sun J, Xu L, Zhao N, Yan M, Li H, Qin P. Nucleosome Assembly Protein 1-Like 3 Enhances Cisplatin Resistance of Ovarian Cancer Cell by Activating Transforming Growth Factor-Beta Pathway. J Interferon Cytokine Res 2020; 40:333-340. [PMID: 32701410 DOI: 10.1089/jir.2020.0022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Chemotherapy resistance is one of the main reasons for tumor-related death. In particular, ovarian cancer patients often acquire drug resistance after chemotherapy. In this study, we found that the histone chaperone, nucleosome assembly protein 1-like 3 (NAP1L3), was significantly upregulated in tissues with cisplatin resistance compared with cisplatin-sensitive tissues. Patients with high NAP1L3 levels had poor prognosis, suggesting that NAP1L3 might regulate ovarian cancer resistance. Colony formation and terminal deoxynulceotidyl transferase nick-end-labeling (TUNEL) assays showed cells with high NAP1L3 had high cisplatin resistance, whereas cells with low NAP1L3 had poor cisplatin resistance. NAP1L3 overexpression significantly increased cisplatin resistance, whereas NAP1L3 knockdown significantly reduced cisplatin resistance, suggesting that NAP1L3 promoted cisplatin resistance. Mechanistically, gene set enrichment analysis and luciferase reporter assays showed that NAP1L3 regulated the transforming growth factor-beta (TGF-β) pathway. NAP1L3 overexpression increased the phosphorylation and nuclear translocation of SMAD family member 2 (SMAD2) and SMAD3, confirming that NAP1L3 activated the TGF-β pathway. Therefore, NAP1L3 might represent a novel target to overcome ovarian cancer chemoresistance.
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Affiliation(s)
- Xiaomei Mo
- Department of Pharmacy, Qingdao Women and Children's Hospital, Qingdao, China
| | - Jinghua Sun
- Gynecological Center, Qingdao Women and Children's Hospital, Qingdao, China
| | - Lujie Xu
- Department of Pharmacy, Qingdao Women and Children's Hospital, Qingdao, China
| | - Na Zhao
- Department of Pharmacy, Qingdao Women and Children's Hospital, Qingdao, China
| | - Meixing Yan
- Department of Pharmacy, Qingdao Women and Children's Hospital, Qingdao, China
| | - Huahui Li
- Department of Laboratory Medicine, Qingdao Municipal Hospital, Qingdao, China
| | - Pengfei Qin
- Department of Pharmacy, Qingdao Women and Children's Hospital, Qingdao, China
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28
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A lectin-based glycomic approach identifies FUT8 as a driver of radioresistance in oesophageal squamous cell carcinoma. Cell Oncol (Dordr) 2020; 43:695-707. [PMID: 32474852 DOI: 10.1007/s13402-020-00517-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 03/30/2020] [Accepted: 04/03/2020] [Indexed: 02/06/2023] Open
Abstract
PURPOSE Radio-resistance is recognized as a main factor in the failure of radiotherapy in oesophageal squamous cell carcinoma (ESCC). Aberrant cell surface glycosylation has been reported to correlate with radio-resistance in different kinds of tumours. However, glycomic alterations and the corresponding enzymes associated with ESCC radio-resistance have not yet been defined. METHODS Two radioresistant cell lines, EC109R and TE-1R, were established from parental ESCC cell lines EC109 and TE-1 by fractionated irradiation. A lectin microarray was used to screen for altered glycan patterns. RNA-sequencing (RNA-seq) was employed to identify differentially expressed glycosyltransferases. Cell Counting Kit-8, colony formation and flow cytometry assays were used to measure cell viability and radiosensitivity. Expression of glycosyltransferase in ESCC tissues was assessed by immunohistochemistry. In vivo radiosensitivity was analysed using a nude mouse xenograft model. Downstream effectors of the enzyme were verified using a lectin-based pull-down assay combined with mass spectrometry. RESULTS We found that EC109R and TE-1R cells were more resistant to irradiation than the parental EC109 and TE-1 cells. Using lectin microarrays combined with RNA sequencing, we found that α1, 6-fucosyltransferase (FUT8) was overexpressed in the radioresistant ESCC cell lines. Both gain- and loss-of-function studies confirmed that FUT8 regulates the sensitivity of ESCC cells to irradiation. Importantly, we found that high FUT8 expression was positively linked to radio-resistance and a poor prognosis in ESCC patients who received radiation therapy. Moreover, FUT8 inhibition suppressed the growth and formation of xenograft tumours in nude mice after irradiation. Using a lectin-based pull-down assay and mass spectrometry, we found that CD147 could be glycosylated by FUT8. As expected, inhibition of CD147 partly reversed FUT8-induced radio-resistance in ESCC cells. CONCLUSIONS Our results indicate that FUT8 functions as a driver of radio-resistance in ESCC by targeting CD147. Therefore, FUT8 may serve as a marker for predicting the response to radiation therapy in patients with ESCC.
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29
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Cheng C, Ding Q, Zhang Z, Wang S, Zhong B, Huang X, Shao Z. PTBP1 modulates osteosarcoma chemoresistance to cisplatin by regulating the expression of the copper transporter SLC31A1. J Cell Mol Med 2020; 24:5274-5289. [PMID: 32207235 PMCID: PMC7205786 DOI: 10.1111/jcmm.15183] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 02/26/2020] [Accepted: 03/06/2020] [Indexed: 12/12/2022] Open
Abstract
Chemoresistance is the main obstacle of treatment in patients with osteosarcoma. RNA‐binding protein PTBP1 has been identified as an oncogene in various cancers. However, the role of PTBP1 in osteosarcoma, especially in chemoresistant osteosarcoma, and the underlying mechanism remain unclear. In this study, we aimed to explore the functions of PTBP1 in chemoresistance of osteosarcoma. We found that PTBP1 was significantly increased in chemotherapeutically insensitive osteosarcoma tissues and cisplatin‐resistant osteosarcoma cell lines (MG‐63CISR and U‐2OSCISR) as compared to chemotherapy‐sensitive osteosarcoma tissues and cell lines. Knock‐down of PTBP1 can enhance the anti‐proliferation and apoptosis‐induced effects of cisplatin in MG‐63CISR and U‐2OSCISR cells. Moreover, PTBP1 knock‐down significantly up‐regulated the expression of the copper transporter SLC31A1, as indicated by transcriptome sequencing. Through RNA immunoprecipitation, dual‐luciferase reporter assay and RNA stability detection, we confirmed that PTBP1 binds to SLC31A1 mRNA and regulates the expression level of SLC31A1 by affecting mRNA stability. Additionally, SLC31A1 silencing abrogated the chemosensitizing effect of PTBP1 knock‐down in MG‐63CISR and U‐2OSCISR cells. Using a nude mouse xenograft model, we further confirmed that PTBP1 knock‐down enhanced chemoresistant osteosarcoma responsiveness to cisplatin treatment in vivo. Collectively, the present study suggests that PTBP1 is a crucial determinant of chemoresistance in osteosarcoma.
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Affiliation(s)
- Cheng Cheng
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiuyue Ding
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhicai Zhang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shangyu Wang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Binlong Zhong
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xin Huang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zengwu Shao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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30
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Ascites from Ovarian Cancer Induces Novel Fucosylated Proteins. CANCER MICROENVIRONMENT 2019; 12:181-195. [PMID: 31267484 DOI: 10.1007/s12307-019-00227-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 05/24/2019] [Indexed: 12/18/2022]
Abstract
Ovarian cancer is considered to be the most lethal type of gynecological cancer. During the advanced stages of ovarian cancer, an accumulation of ascites is observed. Fucosylation has been classified as an abnormal post-translational modification that is present in many diseases, including ovarian cancer. Ovarian cancer cells that are cultured with ascites stimulation change their morphology; concomitantly, the fucosylation process is altered. However, it is not known which fucosylated proteins are modified. The goal of this work was to identify the differentially fucosylated proteins that are expressed by ovarian cancer cell lines that are cultured with ovarian cancer patients' ascites. Aleuria aurantia lectin was used to detect fucosylation, and some changes were observed, especially in the cell membrane. Affinity chromatography and mass spectrometry (MALDI-TOF) were used to identify 6 fucosylated proteins. Four proteins (Intermediate filament family orphan 1 [IFFO1], PHD finger protein 20-like protein 1 [PHF20L1], immunoglobulin gamma 1 heavy chain variable region partial [IGHV1-2], and Zinc finger protein 224 [ZNF224]) were obtained from cell cultures stimulated with ascites, and the other two proteins (Peregrin [BRPF1] and Dystrobrevin alpha [DTNA]) were obtained under normal culture conditions. The fucosylated state of some of these proteins was further analyzed. The experimental results show that the ascites of ovarian cancer patients modulated the fucosylation process. The PHD finger protein 20-like protein 1, Zinc finger protein 224 and Peregrin proteins colocalize with fucosylation at different levels.
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