Mannose impairs tumour growth and enhances chemotherapy

Sierra Gonzalez, P. et al. (2018) Mannose impairs tumour growth and enhances chemotherapy. Nature, 563, pp. 719-723. (doi: 10.1038/s41586-018-0729-3) (PMID:30464341)

Abstract

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.

• Item Type: Articles
• Additional Information: This work was supported by Worldwide Cancer Research (16-1194) and Cancer Research UK (A15816 and A17196).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Baudot, Dr Alice and Ryan, Professor Kevin and Nixon, Mr Colin and Roseweir, Dr Antonia and Edwards, Professor Joanne and Beaumatin, Dr Florian and Barthet, Valentin and Ennis, Dr Darren and Mackay, Dr Gillian and Mrowinska, Ms Agata and O'Prey, Mr James and Gay, David and Mcneish, Professor Iain and Cardaci, Dr Simone and Malviya, Dr Gaurav and Sierra Gonzalez, Pablo and Sansom, Professor Owen
• Authors: Sierra Gonzalez, P., O'Prey, J., Cardaci, S., Barthet, V. J.A., Sakamaki, J.-i., Beaumatin, F., Roseweir, A., Gay, D. M., Mackay, G., Malviya, G., Kania, E., Ritchie, S., Baudot, A. D., Zunino, B., Mrowinska, A., Nixon, C., Ennis, D., Hoyle, A., Millan, D., Mcneish, I. A., Sansom, O. J., Edwards, J., and Ryan, K. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature
• Publisher: Nature Publishing Group
• ISSN: 0028-0836
• ISSN (Online): 1476-4687
• Published Online: 21 November 2018
• Copyright Holders: Copyright © 2018 Springer Nature Limited
• First Published: First published in Nature 563:719-723
• Publisher Policy: Reproduced in accordance with the publisher copyright policy