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Targeting aberrant sialylation and fucosylation in prostate cancer cells using potent metabolic inhibitors

Lookup NU author(s): Maggie Orozco Moreno, Dr Kirsty Hodgson, Kayla Bastian, Emily Archer Goode, Dr Jennifer Munkley

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Aberrant glycosylation is a hallmark of cancer and is not just a consequence, but also a driver of a malignant phenotype. In prostate cancer, changes in fucosylated and sialylated glycans are common and this has important implications for tumor progression, metastasis, and immune evasion. Glycans hold huge translational potential and new therapies targeting tumor-associated glycans are currently being tested in clinical trials for several tumor types. Inhibitors targeting fucosylation and sialylation have been developed and show promise for cancer treatment, but translational development is hampered by safety issues related to systemic adverse effects. Recently, potent metabolic inhibitors of sialylation and fucosylation were designed that reach higher effective concentrations within the cell, thereby rendering them useful tools to study sialylation and fucosylation as potential candidates for therapeutic testing. Here, we investigated the effects of global metabolic inhibitors of fucosylation and sialylation in the context of prostate cancer progression. We find that these inhibitors effectively shut down the synthesis of sialylated and fucosylated glycans to remodel the prostate cancer glycome with only minor apparent side effects on other glycan types. Our results demonstrate that treatment with inhibitors targeting fucosylation or sialylation decreases prostate cancer cell growth and downregulates the expression of genes and proteins important in the trajectory of disease progression. We anticipate our findings will lead to the broader use of metabolic inhibitors to explore the role of fucosylated and sialylated glycans in prostate tumor pathology and may pave the way for the development of new therapies for prostate cancer.


Publication metadata

Author(s): Orozco-Moreno M, Visser EA, Hodgson K, Hipgrave Ederveen AL, Bastian K, Archer Goode E, Öztürk O, Pijnenborg JFA, Eerden N, Moons SJ, Rossing E, Wang N, de Haan N, Büll C, Boltje TJ, Munkley J

Publication type: Article

Publication status: Published

Journal: Glycobiology

Year: 2023

Volume: 33

Issue: 12

Pages: 1155-1171

Print publication date: 01/12/2023

Online publication date: 17/10/2023

Acceptance date: 14/10/2023

Date deposited: 14/05/2024

ISSN (electronic): 1460-2423

Publisher: Oxford University Press

URL: https://doi.org/10.1093/glycob/cwad085

DOI: 10.1093/glycob/cwad085

Data Access Statement: The authors confirm that the data supporting the findings of this study are available within the article and its Supplementary Materials.

PubMed id: 37847613


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Funding

Funder referenceFunder name
6961
Bob Willis Fund
Dutch Research Council (NWO)
ERC-Stg
GlycoEdit, 758913
JGW Patterson Foundation
Mark Foundation
Newcastle Hospitals Special Trustees
Prostate Cancer Research
RIA21-ST2-006
Prostate Cancer UK
RIA16-ST2-011Prostate Cancer UK (Formerly Prostate Cancer Charity)
VI.Veni.202.045

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