Regulation of GLUT Transporters by Flavonoids in Androgen-Sensitive and -Insensitive Prostate Cancer Cells

Abstract

Cancer cells show different metabolic requirements from normal cells. In prostate cancer, particularly, glycolytic metabolism differs in androgen-responsive and nonresponsive cells. In addition, some natural compounds with antiproliferative activities are able to modify glucose entry into cells by either modulating glucose transporter (GLUT) expression or by altering glucose binding. The aim of this work was to study the regulation of some GLUTs (GLUT1 and GLUT4) in both androgen-sensitive (LNCaP) and -insensitive (PC-3) prostate cancer cells by 4 structurally different flavonoids (ie, genistein, phloretin, apigenin, and daidzein). Glucose uptake was measured using nonradiolabeled 2-deoxyglucose. The evaluation of protein levels as well as subcellular distribution of GLUT1/4 were analyzed by Western blot and immunocytochemistry, respectively. Androgen-insensitive LNCaP-R and androgen-sensitive PC-3-AR cells were used to study the effect of androgen signaling. Additionally, a docking simulation was employed to compare interactions between flavonoids and XylE, a bacterial homolog of GLUT1 to -4. Results show for the first time the presence of functionally relevant GLUT4 in prostate cancer cells. Furthermore, differences in GLUT1 and GLUT4 levels and glucose uptake were found, without differences on subcellular distribution, after incubation with flavonoids. Docking simulation showed that all compounds interact with the same location of transporters. More importantly, differences between androgen-sensitive and -insensitive prostate cancer cells were found in both GLUT protein levels and glucose uptake. Thus, phenotypic characteristics of prostate cancer cells are responsible for the different effects of these flavonoids in glucose uptake and in GLUT expression rather than their structural differences, with the most effective in reducing cell growth being the highest in modifying glucose uptake and GLUT levels.

The dark side of glucose transporters in prostate cancer: Are they a new feature to characterize carcinomas?

“…62 This overexpression seems to be dependent on hypoxia more than androgenic regulation. 64 Regarding its intracellular localization, GLUT1 was also found in the Golgi apparatus where it could have a role in supplying glucose to the prostatic fluid. 24 Furthermore, GLUT1 is involved in the increase in glucose uptake by inflammatory cells in PCa, 63 and it was recently described that this isoform overexpression in PCa might be mediated by the reduced levels of microRNA-132.…”

“…24 Furthermore, GLUT1 is involved in the increase in glucose uptake by inflammatory cells in PCa, 63 and it was recently described that this isoform overexpression in PCa might be mediated by the reduced levels of microRNA-132. 64 Regarding its intracellular localization, GLUT1 was also found in the Golgi apparatus where it could have a role in supplying glucose to the prostatic fluid. 65 On the other hand, GLUT3 is activated via caveolin-1 in AR-negative cells 66 and GLUT12, which is also considered an insulin-dependent transporter, was found in PCa but not in non-tumor samples, 65 suggesting a similar role than other insulin-dependent transporters, such as GLUT4, in tumorigenesis.…”

Evidence to Support the Anti-Cancer Effect of Olive Leaf Extract and Future Directions

“…The glucose moiety in oleuropein may facilitate its diffusion into these cells in precedence to normal cells and therefore result in a greater inhibitory effect on cancer versus normal cells. Another study has indicated that the olive flavonoid apigenin is able to reduce the expression of GLUT1 in prostate cancer cell lines thereby inhibiting proliferation of the cancer [29]. …”

“…The addition of leaves increase the phenolic and chlorophyll content of the oil but also the organoleptic traits as measured in volunteer taste tests [24]. Components of OLE that are not detected in the oil from the fruit include several flavonoids, namely luteolin and apigenin, which have demonstrated anti-cancer properties [25,26,27,28,29]. In addition, the structure of phenolics differs between the olive fruit and leaf, with OLE containing a higher proportion with a glycoside moiety (Figure 2 and Table 1) [19].…”

Roles of facilitative glucose transporter GLUT1 in [18F]FDG positron emission tomography (PET) imaging of human diseases

“…The flavanoids genistein, phloretin, apigenin, and daidzein have different effects on reducing GLUT1 expression and glucose uptake in androgen responsive versus non-responsive prostate cancer cells and therefore different effects on reducing cell growth [128].…”