Mannose impairs tumour growth and enhances chemotherapy
File(s)
Supporting information
Accepted version
Author(s)
Type
Journal Article
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.
Date Issued
2018-11-21
Date Acceptance
2018-10-05
Citation
Nature, 2018, 563, pp.719-723
ISSN
0028-0836
Publisher
Nature Publishing Group
Start Page
719
End Page
723
Journal / Book Title
Nature
Volume
563
Copyright Statement
© 2018 Springer Nature Limited. All rights reserved.
Sponsor
Cancer Research UK
Identifier
https://www.nature.com/articles/s41586-018-0729-3
Grant Number
RG71079
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
CELL-SURVIVAL
METABOLISM
AUTOPHAGY
CANCER
RESISTANCE
HALLMARKS
APOPTOSIS
Administration, Oral
Animals
Antineoplastic Agents
Apoptosis
Biomarkers, Tumor
Body Weight
Cell Line, Tumor
Cell Proliferation
Down-Regulation
Drug Synergism
Female
Glucose
Glycolysis
Humans
Mannose
Mannose-6-Phosphate Isomerase
Mannosephosphates
Mice
Mice, Inbred C57BL
Mice, Nude
Myeloid Cell Leukemia Sequence 1 Protein
Neoplasms
RNA Interference
bcl-X Protein
Cell Line, Tumor
Animals
Mice, Inbred C57BL
Humans
Mice
Mice, Nude
Neoplasms
Body Weight
Mannose-6-Phosphate Isomerase
Glucose
Mannose
Mannosephosphates
Antineoplastic Agents
Administration, Oral
Apoptosis
Cell Proliferation
Down-Regulation
RNA Interference
Glycolysis
Drug Synergism
Female
bcl-X Protein
Myeloid Cell Leukemia Sequence 1 Protein
Biomarkers, Tumor
General Science & Technology
Publication Status
Published
Date Publish Online
2018-11-21