Enhanced Fructose Utilization Mediated by SLC2A5 Is a Unique Metabolic Feature of Acute Myeloid Leukemia with Therapeutic Potential

Abstract

SUMMARY Rapidly proliferating leukemic progenitor cells consume substantial glucose that may lead to glucose insufficiency in bone marrow. We show that acute myeloid leukemia (AML) cells are prone to fructose utilization with an upregulated fructose transporter GLUT5, compensating for glucose deficiency. Notably, AML patients with upregulated transcription of GLUT5-encoding gene SLC2A5 or increased fructose utilization have poor outcomes. Pharmacological blockage of fructose uptake ameliorates leukemic phenotypes and potentiates the cytotoxicity of antileukemic agent, Ara-C. In conclusion, this study highlights enhanced fructose utilization as a metabolic feature of AML and a potential therapeutic target.

A Comparison of Gene Expression Profiles between Glucocorticoid Responder and Non-Responder Bovine Trabecular Meshwork Cells Using RNA Sequencing

“…The solute carrier family 2 member 5 ( SLC2A5 ) gene encodes the fructose transporter GLUT5, and the aralkylamine N-acetyltransferase (AANAT) gene encodes an enzyme that plays a role in melatonin synthesis. Increased GLUT5 is found in tumor cells as a feature of their metabolism [68], while changes in AANAT is associated with depression [69]. Until now, most of the research of GIG are at cellular and molecular biology levels.…”

Application of Mono‐ and Disaccharides in Drug Targeting and Efficacy

“…Alternatively, co‐administration of 2‐DG with either doxorubicin, sorafenib, adriamycin, or paclitaxel was observed to increase the therapeutic effectiveness of each of these drugs against various cancer cells such as pancreatic, papillary thyroid carcinoma, and neuroblastoma cells . 2‐Fluoro‐2‐deoxyglucose (FDG, 20 ), another glucose analogue, conjugated with 5‐fluorouracil (5‐FU) or chlorambucil (CLB), significantly increased the activity of these advanced antitumor drugs . This can be explained by two main mechanisms: one is that high glucose consumption caused by the increased rate of glycolysis in malignant cells may promote an increased uptake of 2‐DG and FDG in tumor cells over normal cells; another is that 2‐DG and FDG interfere with cellular energy metabolism, giving rise to cancer cell apoptosis .…”

“…[86][87][88][89][90] 20), another glucose analogue, conjugated with 5-fluorouracil (5-FU)o rchlorambucil( CLB), significantly increased the activity of these advanced antitumord rugs. [91][92][93] This can be explained by two main mechanisms:o ne is that high glucose consumption caused by the increased rate of glycolysis in malignant cells may promote an increased uptake of 2-DG and FDG in tumor cells over normal cells;a nother is that 2-DG and FDG interfere with cellular energy metabolism, giving rise to cancer cell apoptosis. [93] 2,5-Anhydro-d-mannitol (2,5-AM, 21) ( Figure 5), af ructose analogue with high affinity for GLUT5, was found to be effective at killing acute myeloid leukemia (AML) cells by pharmacologically blocking fructose uptake.…”

“…[91][92][93] This can be explained by two main mechanisms:o ne is that high glucose consumption caused by the increased rate of glycolysis in malignant cells may promote an increased uptake of 2-DG and FDG in tumor cells over normal cells;a nother is that 2-DG and FDG interfere with cellular energy metabolism, giving rise to cancer cell apoptosis. [93] 2,5-Anhydro-d-mannitol (2,5-AM, 21) ( Figure 5), af ructose analogue with high affinity for GLUT5, was found to be effective at killing acute myeloid leukemia (AML) cells by pharmacologically blocking fructose uptake. Moreover,as ignificant synergistic effect was observed between 2,5-AM and arabinofuranosyl cytidine( Ara-C).…”

Spherical and Worm‐Like Micelles from Fructose‐Functionalized Polyether Block Copolymers

“…Most recently, GLUT5 shifted into the focus of interest because it shows fructose specific binding and uptake and its structure could be determined recently . Even if controversy discussed in literature, overexpression of GLUT5 in breast cancer cells and tissue as well as in acute myeloid leukemia cells can be assumed . The fact that this can be exploited to selectively target cells with nanostructures functionalized with fructose residues could be first shown for micelles of acrylate‐based block copolymers and triple negative breast cancer cells .…”