Statins Impair Glucose Uptake in Tumor Cells

Abstract

Statins, HMG-CoA reductase inhibitors, are used in the prevention and treatment of cardiovascular diseases owing to their lipid-lowering effects. Previous studies revealed that, by modulating membrane cholesterol content, statins could induce conformational changes in cluster of differentiation 20 (CD20) tetraspanin. The aim of the presented study was to investigate the influence of statins on glucose transporter 1 (GLUT1)-mediated glucose uptake in tumor cells. We observed a significant concentration- and time-dependent decrease in glucose analogs' uptake in several tumor cell lines incubated with statins. This effect was reversible with restitution of cholesterol synthesis pathway with mevalonic acid as well as with supplementation of plasma membrane with exogenous cholesterol. Statins did not change overall GLUT1 expression at neither transcriptional nor protein levels. An exploratory clinical trial revealed that statin treatment decreased glucose uptake in peripheral blood leukocytes and lowered (18)F-fluorodeoxyglucose ((18)F-FDG) uptake by tumor masses in a mantle cell lymphoma patient. A bioinformatics analysis was used to predict the structure of human GLUT1 and to identify putative cholesterol-binding motifs in its juxtamembrane fragment. Altogether, the influence of statins on glucose uptake seems to be of clinical significance. By inhibiting (18)F-FDG uptake, statins can negatively affect the sensitivity of positron emission tomography, a diagnostic procedure frequently used in oncology.

Statins impair glucose uptake in tumor cells

“…9 The emergence of statins as effective cholesterol-lowering agents during hypercholesterolemia also brings with it anticancer benefits beyond cardiovascular protection. The findings of Malenda et al 8 reported in Neoplasia reveal the effect of statins on glucose metabolism of tumor cells. Although earlier reports have indicated that statins can promote apoptosis or, arrest proliferation in cancer cells; in this report the investigators demonstrate using sound methodology that pre-incubation of tumor cells with statins impair glucose uptake.…”

“…Conversely, a prolonged blockade of glucose uptake would necessitate the cells to curtail or temporarily arrest all major energy-dependent synthetic and secretory activities, ultimately leading to cell death. Since Malenda et al, 8 haven't observed any cell death it is likely the cells are under transient metabolic arrest. Such an arrest in protein synthesis or translation could be assessed by several approaches, such as 35 S-methionine incorporation.…”

The effect of statins on cancer cells—review

“…In tumor cells, the expression of the glucose transporter, GLUT-1, is frequently upregulated, as tumor cells require a high glucose supply for their increased metabolic demands. Studies using statins performed on human Burkitt lymphoma, human follicular lymphoma, and human colon adenocarcinoma have shown that statins are not able to inhibit expression of GLUT proteins, but by inhibition of cholesterol synthesis, they could induce conformational changes in GLUT proteins that possess multiple membrane-spanning domains [59]. It was previously shown that cholesterol can associate with a number of membrane proteins via covalent or noncovalent interactions and also induces condensation of membrane lipids and formation of membrane rafts.…”

Statin use is safe and does not impact prognosis in patient with de novo follicular lymphoma treated with immunochemotherapy: An exploratory analysis of the PRIMA cohort study

“…In lymphoma, statins were recently shown to induce apoptosis by promoting ROS generation and Akt, Erk and p38 signalling pathway regulation . Malenda et al also demonstrated that HMG‐CoA reductase inhibitors impair glucose uptake in tumor cells possibly by inhibiting a putative cholesterol‐binding motif in the juxtamembrane fragment of glucose transporter 1 (GLUT‐1) .…”