Sialylation Inhibition Can Partially Revert Acquired Resistance to Enzalutamide in Prostate Cancer Cells

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