Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UNIPROT:P10415 (
Bcl-2
)
33,771
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
It is now well established that tumours undergo changes in cellular metabolism
1
. As this can reveal tumour cell vulnerabilities and because many tumours exhibit enhanced glucose uptake
2
, 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 glucose
3
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.
...
PMID:Mannose impairs tumour growth and enhances chemotherapy. 3046 41
