PTEN regulates plasma membrane expression of glucose transporter 1 and glucose uptake in thyroid cancer cells

Abstract

Glucose represents an important source of energy for the cells. Proliferating cancer cells consume elevated quantity of glucose, which is converted into lactate regardless of the presence of oxygen. This phenomenon, known as the Warburg effect, has been proven to be useful for imaging metabolically active tumours in cancer patients by 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET). Glucose is internalised in the cells by glucose transporters (GLUTs) belonging to the GLUT family. GLUT1 (SLC2A1) is the most prevalent isoform in more aggressive and less differentiated thyroid cancer histotypes. In a previous work, we found that loss of expression of PTEN was associated with increased expression of GLUT1 on the plasma membrane (PM) and probability of detecting thyroid incidentalomas by FDG-PET. Herein, we investigated the molecular pathways that govern the expression of GLUT1 on the PM and the glucose uptake in WRO (expressing WT PTEN) and FTC133 (PTEN null) follicular thyroid cancer cells cultured under glucose-depleted conditions. The membrane expression of GLUT1 was enhanced in glucose-deprived cells. Through genetic manipulations of PTEN expression, we could demonstrate that the lack of this oncosuppressor has a dominant effect on the membrane expression of GLUT1 and glucose uptake. We conclude that loss of function of PTEN increases the probability of cancer detection by FDG-PET or other glucose-based imaging diagnosis.

PTEN dephosphorylates AKT to prevent the expression of GLUT1 on plasmamembrane and to limit glucose consumption in cancer cells

“…The above notions underlay the need to improve our knowledge on the pathways that control the expression and translocation of GLUT1 on the plasmamembrane of cancer cells, as this can pave the way for new metabolic therapies [43–45]. The PI3KC1-AKT pathway plays a major role in driving the translocation of GLUT1 from para-golgian vesicles onto the plasmamembrane [20], as also shown in the present study. This pathway is frequently up-regulated in cancer cells because of activating mutations in the PI3KC1 and/or AKT genes.…”

“…To confirm definitively that wt and G129E PTEN are able to interact physically with AKT we performed a co-immunoprecipitation test. To avoid any possible interference with endogenous PTEN, this experiment was performed in the thyroid cancer cell line FTC-133 that is known to be PTEN null and to express high level of phospho-AKT [20]. The cells were transfected with either the wt or the G129E or the C124S PTEN mutant isoforms tagged with HIS.…”

“…A clear involvement of the PI3k class I (PI3KC1)-AKT pathway and of the AKT downstream effector AS160 (a rab GTPase activator) has been demonstrated in the case of GLUT4 translocation [18, 19]. More recently, we have shown that this pathway is also involved in the cell surface exposure of GLUT1 in thyroid cancer cells [20]. PTEN (Phosphatase and TENsin homolog deleted on chromosome ten), the oncosuppressor protein with dual lipid and protein phosphatase activity, has been shown to contrast the uptake and the large glycolytic consumption of glucose observed in proliferating cancer cells [21].…”

“…PTEN (Phosphatase and TENsin homolog deleted on chromosome ten), the oncosuppressor protein with dual lipid and protein phosphatase activity, has been shown to contrast the uptake and the large glycolytic consumption of glucose observed in proliferating cancer cells [21]. Indeed, PTEN can inhibit the activation of AKT, thus preventing GLUT1 expression on the plasmamembrane [20]. This effect has been attributed to the lipid phosphatase activity of PTEN that reduces the availability of Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), the phosphate donor for the phosphorylation of AKT.…”

Endothelial and circulating C19MC microRNAs are biomarkers of infantile hemangioma

“…In that study, knockdown of AKT3 , but not AKT1 , was observed to stimulate IH endothelial cell sprouting and migration in vitro, and forced expression of an AKT transgene induced GLUT-1 expression in mouse endothelial cells engrafted on nude mice. Phosphorylated AKT is known to drive SLC2A1 expression in multiple cell types (49–51), and cytoplasmic sequestration of GLUT-1 has been shown to be PTEN dependent (52). Hence, the plasma membrane GLUT-1 expression that is diagnostic of IH may result at least in part from the targeting of PTEN by C19MC miRNAs and resultant AKT activation.…”