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Lookup NU author(s): Maggie Orozco Moreno, Dr Kirsty Hodgson, Amirah Nabilah, Meera Murali, Jess Peng, Professor David Elliott, Dr Jennifer Munkley
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024 by the authors.Prostate cancer is a lethal solid malignancy and a leading cause of cancer-related deaths in males worldwide. Treatments, including radical prostatectomy, radiotherapy, and hormone therapy, are available and have improved patient survival; however, recurrence remains a huge clinical challenge. Enzalutamide is a second-generation androgen receptor antagonist that is used to treat castrate-resistant prostate cancer. Among patients who initially respond to enzalutamide, virtually all acquire secondary resistance, and an improved understanding of the mechanisms involved is urgently needed. Aberrant glycosylation, and, in particular, alterations to sialylated glycans, have been reported as mediators of therapy resistance in cancer, but a link between tumour-associated glycans and resistance to therapy in prostate cancer has not yet been investigated. Here, using cell line models, we show that prostate cancer cells with acquired resistance to enzalutamide therapy have an upregulation of the sialyltransferase ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) and increased levels of α2,6-sialylated N-glycans. Furthermore, using the sialyltransferase inhibitor P-SiaFNEtoc, we discover that acquired resistance to enzalutamide can be partially reversed by combining enzalutamide therapy with sialic acid blockade. Our findings identify a potential role for ST6GAL1-mediated aberrant sialylation in acquired resistance to enzalutamide therapy for prostate cancer and suggest that sialic acid blockade in combination with enzalutamide may represent a novel therapeutic approach in patients with advanced disease. Our study also highlights the potential to bridge the fields of cancer biology and glycobiology to develop novel combination therapies for prostate cancer.
Author(s): Goode EA, Orozco-Moreno M, Hodgson K, Nabilah A, Murali M, Peng Z, Merx J, Rossing E, Pijnenborg JFA, Boltje TJ, Wang N, Elliott DJ, Munkley J
Publication type: Article
Publication status: Published
Journal: Cancers
Year: 2024
Volume: 16
Issue: 17
Print publication date: 01/09/2024
Online publication date: 24/08/2024
Acceptance date: 22/08/2024
Date deposited: 30/09/2024
ISSN (electronic): 2072-6694
Publisher: Multidisciplinary Digital Publishing Institute (MDPI)
URL: https://doi.org/10.3390/cancers16172953
DOI: 10.3390/cancers16172953
Data Access Statement: The authors confirm that the data supporting the findings of this study are available within the article and its Supplementary Materials. https://www.mdpi.com/2072-6694/16/17/2953#app1-cancers-16-02953
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