Quercetin inhibits glucose transport by binding to an exofacial site on GLUT1

Abstract

Quercetin, a common dietary flavone, is a competitive inhibitor of glucose uptake and is also thought to be transported into cells by GLUT1. In this study, we confirm that quercetin is a competitive inhibitor of GLUT1 and also demonstrate that newly synthesized compounds, WZB-117 and BAY-876 are robust inhibitors of GLUT1 in L929 cells. To measure quercetin interaction with L929 cells, we develop a new fluorescent assay using flow cytometry. The binding of quercetin and its inhibitory effects on 2-deoxyglucose (2DG) uptake showed nearly identical dose dependent effects, with both having maximum effects between 50 and 100 μM and similar half maximum effects at 8.9 and 8.5 μM respectively. The interaction of quercetin was rapid with t of 54 s and the onset and loss of its inhibitory effects on 2DG uptake were equally fast. This suggests that either quercetin is simply binding to surface GLUT1 or its transport in and out of the cell reaches equilibrium very quickly. If quercetin is transported, the co-incubation of quercetin with other glucose inhibitors should block quercetin uptake. However, we observed that WZB-117, an exofacial binding inhibitor of GLUT1 reduced quercetin interaction, while cytochalasin B, an endofacial binding inhibitor, enhanced quercetin interaction, and BAY-876 had no effect on quercetin interaction. Taken together, these data are more consistent with quercetin simply binding to GLUT1, but not actually being transported into L929 cells via the glucose channel in GLUT1.

Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast Cancer

“…Several compounds have shown their capability to bind to the different domains of GLUT transporters and thus influence the activity and function of the transporters. For example, genistein binds to the exofacial side of GLUT transporter, whereas quercetin, tyrphostin A47, and tyrphostin B46 bind to the cytoplasmic side of the cell ( Table 1 ) [ 74 , 75 ]. A small molecule inhibitor WZB117 and resveratrol can directly inhibit GLUT-1 transporter [ 76 , 77 ], whereas genistein has been reported to be a competitive inhibitor of GLUT-1 transporter, thus affects transport of hexoses and dehydroascorbic acid.…”

Ovarian Cancer Relies on Glucose Transporter 1 to Fuel Glycolysis and Growth: Anti-Tumor Activity of BAY-876

“…Among small-molecule GLUT1 inhibitors [23,26,27,28,29,30,31,32], STF-31 [23] and WZB117 [26] were reported to inhibit GLUT1-mediated glucose uptake at low µM concentrations and to show some anti-cancer activities in xenograft tumor models. However, the GLUT1 selectivity and potencies of these earlier GLUT1 inhibitors are controversial [33,34].…”

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“…Встановлений нами сприятливий вплив кверцетину на стан вуглеводного обміну у хворих літнього віку з МС можна пояснити його захисною дією на β-клітини острівців підшлункової залози [5], покращенням чутливості до інсуліну [4,6,7], посиленням проліферації β-клітин, збільшенням секреції інсуліну [5,7]. Крім того, кверцетин підвищує експресію транспортерів глюко-зи (GLUT1, GLUT4), посилює поглинання глюкози міоцитами шляхом стимулювання протеїнкінази та діє на транспорт глюкози й інсулін-рецепторний сигнал подібно до розіглітазону, як агоніст гама PPARγ [8,9]. Чутливість до інсуліну зростає частково і за рахунок підвищення експресії адипонектину [10,11] та активації SIRT1 [6].…”