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Sialylation Inhibition Can Partially Revert Acquired Resistance to Enzalutamide in Prostate Cancer Cells
by
, , , , ,
Emily Archer Goode
1, 
Margarita Orozco-Moreno
1,
Kirsty Hodgson
1,
Amirah Nabilah
1,
Meera Murali
1,
Ziqian Peng
1,
Jona Merx
2,
Emiel Rossing
3,
Johan F. A. Pijnenborg
3,
Thomas J. Boltje
2,3,
Ning Wang
4,5,
David J. Elliott
1 and
Jennifer Munkley
1,* 1
Newcastle University Centre for Cancer, Newcastle University Institute of Biosciences, Newcastle NE1 3BZ, UK
2
Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University, 6525 XZ Nijmegen, The Netherlands
3
GlycoTherapeutics B.V., 6511 AJ Nijmegen, The Netherlands
4
The Mellanby Centre for Musculoskeletal Research, Division of Clinical Medicine, The University of Sheffield, Sheffield S10 2TN, UK
5
Leicester Cancer Research Centre, Department of Genetics and Genome Biology, University of Leicester, Leicester LE2 7LX, UK
*
Author to whom correspondence should be addressed.
Cancers 2024, 16(17), 2953; https://doi.org/10.3390/cancers16172953 (registering DOI)
Submission received: 18 July 2024
/
Revised: 8 August 2024
/
Accepted: 22 August 2024
/
Published: 24 August 2024
(This article belongs to the Special Issue The Prevention and Treatment of Prostate Cancer)
Simple Summary
Prostate cancer is the most common cancer in men and a major cause of cancer-related deaths around the world. Prostate cancer that has spread to other parts of the body (advanced prostate cancer) is often treated with a drug called enzalutamide, which is a type of hormone therapy. Enzalutamide works by blocking the effect of the testosterone hormone on prostate cancer cells to stop them from growing. While this can be effective for several years, unfortunately, many patients being treated with enzalutamide eventually go on to become resistant to treatment, and the therapy stops working. Here, we show that prostate cancer cells that have become resistant to enzalutamide have increased levels of a type of sugar (known as sialic acid) on their surfaces. We set out to test whether stripping sialic acid from the surface of prostate cancer cells could help keep enzalutamide working for longer. Excitingly, our experiments show that treating prostate cancer cells with a drug to block sialic acid can partially reverse enzalutamide resistance. These findings suggest that drugs targeting sialic acid could be used in combination with enzalutamide therapy to disarm drug resistance and provide urgently needed new treatment options for men with prostate cancer.
Abstract
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.
