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 tumour progression, metastasis, and immune evasion. Glycans hold huge translational potential and new therapies targeting tumour-associated glycans are currently being tested in clinical trials for several tumour 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 tumour pathology and may pave the way for the development of new therapies for prostate cancer.

中文翻译：

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使用有效的代谢抑制剂针对前列腺癌细胞中的异常唾液酸化和岩藻糖基化。

异常糖基化是癌症的一个标志，不仅是癌症的结果，也是恶性表型的驱动因素。在前列腺癌中，岩藻糖基化和唾液酸化聚糖的变化很常见，这对肿瘤进展、转移和免疫逃避具有重要意义。聚糖具有巨大的转化潜力，针对肿瘤相关聚糖的新疗法目前正在针对多种肿瘤类型的临床试验中进行测试。针对岩藻糖基化和唾液酸化的抑制剂已经开发出来，并显示出用于癌症治疗的前景，但转化开发受到与全身不良反应相关的安全问题的阻碍。最近，设计了有效的唾液酸化和岩藻糖基化代谢抑制剂，可在细胞内达到更高的有效浓度，从而使它们成为研究唾液酸化和岩藻糖基化的有用工具，作为治疗测试的潜在候选者。在这里，我们研究了岩藻糖基化和唾液酸化的整体代谢抑制剂在前列腺癌进展中的作用。我们发现这些抑制剂有效地关闭唾液酸化和岩藻糖化聚糖的合成，以重塑前列腺癌糖组，而对其他聚糖类型仅产生轻微的明显副作用。我们的结果表明，使用针对岩藻糖基化或唾液酸化的抑制剂治疗可减少前列腺癌细胞的生长，并下调在疾病进展轨迹中重要的基因和蛋白质的表达。我们预计我们的发现将导致代谢抑制剂的更广泛使用，以探索岩藻糖基化和唾液酸化聚糖在前列腺肿瘤病理学中的作用，并可能为前列腺癌新疗法的开发铺平道路。