The monosaccharide mannose inhibits tumor glycolysis and enhances tumor response to chemotherapy.
Major finding: The monosaccharide mannose inhibits tumor glycolysis and enhances tumor response to chemotherapy.
Mechanism: Uptake of mannose by glucose transporters drives the accumulation of mannose-6-phosphate.
Impact: Mannose supplementation may be an efficacious therapy for patients with PMI-low tumors.
Tumor metabolism is altered in order to meet the bioenergetic needs of rapidly growing tumors, resulting in a dependency upon glycolysis. To ascertain the impact of other sugars on tumor growth, Gonzalez and colleagues monitored the growth of cancer cell lines in media supplemented with different hexoses and found that mannose was the only sugar that exhibited significant growth-inhibitory properties. Mannose induced the intracellular accumulation of mannose-6-phosphate and the intracellular pools of mannose and glucose and was shown to be responsible for the majority of the mannose-induced accumulation of mannose-6-phosphate as well as decreased lactate production and glycolytic intermediates, particularly those involved in the TCA cycle, the pentose phosphate pathway, and glycan synthesis. While mannose monotherapy had no effect on cell viability, treatment with mannose and either cisplatin or doxorubicin resulted in increased cell death compared to chemotherapy alone due to increased apoptosis. Mechanistically, mannose enhanced the proapoptotic effects of chemotherapy in a Noxa/BCL-XL/MCL1–dependent manner. Consistent with these findings, treatment of tumor-bearing mice with mannose (by oral gavage and/or addition to the drinking water) decreased both glucose uptake and retention by tumors and tumor growth, enhanced tumor response to doxorubicin, and increased survival. Profiling of sugar metabolism enzymes in mannose-sensitive and mannose-insensitive cancer cell lines demonstrated that expression of phosphomannose isomerase (PMI; encoded by MPI), which catalyzes the reversible interconversion of mannose-6-phosphate and fructose-6-phosphate, was inversely correlated with mannose sensitivity. MPI knockdown sensitized mannose-insensitive cell lines to mannose treatment in vitro and in vivo; moreover, it was shown that human colorectal tumors exhibited low levels of PMI, and treatment of murine models of colon tumors with mannose resulted in decreased tumor burden. Taken together, these results describe the role of mannose in tumor metabolism and suggest that mannose treatment is a potential therapy for patients with tumors expressing low levels of PMI.
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