title: 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.
authors.affiliation: Departamento de Morfologia y Biologia Celular, Instituto Universitario de Oncologia del Principado de Asturias, Universidad de Oviedo, Facultad de Medicina, 33006 Oviedo, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Gonzalez-Menendez
authors.forename: David
authors.initials: D
authors.lastname: Hevia
authors.forename: Aida
authors.initials: A
authors.lastname: Rodriguez-Garcia
authors.forename: Juan C
authors.initials: JC
authors.lastname: Mayo
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Sainz
mesh_terms: D000728:Androgens / Q000378:metabolism*; D001665:Binding Sites; D045744:Cell Line, Tumor; D005419:Flavonoids / Q000737:chemistry / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*
chemical_list: D000728:Androgens; D005419:Flavonoids; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; C495677:SLC2A1 protein, human; C495692:SLC2A4 protein, human; D005947:Glucose