It is now well established that tumours undergo changes in cellular metabolism1. As this can reveal tumour cell vulnerabilities and because many tumours exhibit enhanced glucose uptake2, we have been interested in how tumour cells respond to different forms of sugar. Here we report that the monosaccharide mannose causes growth retardation in several tumour types in vitro, and enhances cell death in response to major forms of chemotherapy. We then show that these effects also occur in vivo in mice following the oral administration of mannose, without significantly affecting the weight and health of the animals. Mechanistically, mannose is taken up by the same transporter(s) as glucose3 but accumulates as mannose-6-phosphate in cells, and this impairs the further metabolism of glucose in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway and glycan synthesis. As a result, the administration of mannose in combination with conventional chemotherapy affects levels of anti-apoptotic proteins of the Bcl-2 family, leading to sensitization to cell death. Finally we show that susceptibility to mannose is dependent on the levels of phosphomannose isomerase (PMI). Cells with low levels of PMI are sensitive to mannose, whereas cells with high levels are resistant, but can be made sensitive by RNA-interference-mediated depletion of the enzyme. In addition, we use tissue microarrays to show that PMI levels also vary greatly between different patients and different tumour types, indicating that PMI levels could be used as a biomarker to direct the successful administration of mannose. We consider that the administration of mannose could be a simple, safe and selective therapy in the treatment of cancer, and could be applicable to multiple tumour types.Mannose reduces the growth of tumour cells by impairing the metabolism of glucose, and enhances cell death when used in combination with conventional chemotherapy.

中文翻译：

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甘露糖损害肿瘤生长并增强化疗

现在已经确定肿瘤会发生细胞代谢的变化1。由于这可以揭示肿瘤细胞的脆弱性，并且由于许多肿瘤表现出增强的葡萄糖摄取 2，我们一直对肿瘤细胞如何对不同形式的糖做出反应感兴趣。在这里我们报告单糖甘露糖在体外导致几种肿瘤类型的生长迟缓，并增强细胞死亡以响应主要形式的化疗。然后我们表明，在口服甘露糖后，这些效应在小鼠体内也发生，而不会显着影响动物的体重和健康。从机制上讲，甘露糖被与葡萄糖相同的转运蛋白吸收，但在细胞中以 6-磷酸甘露糖的形式积累，这会损害糖酵解中葡萄糖的进一步代谢，三羧酸循环，磷酸戊糖途径和聚糖合成。因此，甘露糖联合常规化疗会影响 Bcl-2 家族抗凋亡蛋白的水平，导致对细胞死亡的敏感性。最后，我们表明对甘露糖的敏感性取决于磷酸甘露糖异构酶 (PMI) 的水平。PMI 水平低的细胞对甘露糖敏感，而高水平的细胞具有抗性，但可以通过 RNA 干扰介导的酶耗竭而变得敏感。此外，我们使用组织微阵列显示，不同患者和不同肿瘤类型之间的 PMI 水平也有很大差异，表明 PMI 水平可以用作指导甘露糖成功给药的生物标志物。我们认为甘露糖的管理可以是一个简单的，