Mannose impairs tumour growth and enhances chemotherapy

Pablo Sierra Gonzalez, James O’Prey, Simone Cardaci, Valentin J. A. Barthet, Jun-ichi Sakamaki, Florian Beaumatin, Antonia Roseweir, David M. Gay, Gillian Mackay, Gaurav Malviya, Elżbieta Kania, Shona Ritchie, Alice D. Baudot, Barbara Zunino, Agata Mrowinska, Colin Nixon, Darren Ennis, Aoisha Hoyle, David Millan, Iain A. McNeish, Owen J. Sansom, Joanne Edwards and Kevin M. Ryan ()
Additional contact information
Pablo Sierra Gonzalez: Cancer Research UK Beatson Institute
James O’Prey: Cancer Research UK Beatson Institute
Simone Cardaci: Cancer Research UK Beatson Institute
Valentin J. A. Barthet: Cancer Research UK Beatson Institute
Jun-ichi Sakamaki: Cancer Research UK Beatson Institute
Florian Beaumatin: Cancer Research UK Beatson Institute
Antonia Roseweir: University of Glasgow
David M. Gay: Cancer Research UK Beatson Institute
Gillian Mackay: Cancer Research UK Beatson Institute
Gaurav Malviya: Cancer Research UK Beatson Institute
Elżbieta Kania: Cancer Research UK Beatson Institute
Shona Ritchie: Cancer Research UK Beatson Institute
Alice D. Baudot: Cancer Research UK Beatson Institute
Barbara Zunino: Cancer Research UK Beatson Institute
Agata Mrowinska: Cancer Research UK Beatson Institute
Colin Nixon: Cancer Research UK Beatson Institute
Darren Ennis: University of Glasgow
Aoisha Hoyle: Queen Elizabeth University Hospital
David Millan: Queen Elizabeth University Hospital
Iain A. McNeish: University of Glasgow
Owen J. Sansom: Cancer Research UK Beatson Institute
Joanne Edwards: University of Glasgow
Kevin M. Ryan: Cancer Research UK Beatson Institute

Nature, 2018, vol. 563, issue 7733, 719-723

Abstract: 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.

Keywords: Phosphomannose Isomerase; Mannose Treatment; Metabolic Extraction; Mannose-containing Medium; Mouse Lewis Lung Carcinoma Cells (search for similar items in EconPapers)
Date: 2018
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DOI: 10.1038/s41586-018-0729-3

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