title: Apigenin down-regulates the hypoxia response genes: HIF-1α, GLUT-1, and VEGF in human pancreatic cancer cells.
abstract: BACKGROUND
  The flavonoid apigenin exhibits anti-proliferative and anti-angiogenic activities. Our objective was to evaluate the effect of apigenin on hypoxia responsive genes important in pancreatic cancer cell proliferation.
  
  
  METHODS
  Immunohistochemistry for GLUT-1 expression was conducted on human pancreatic cancer samples and adjacent controls. Real-time RT-PCR, Western blot analysis, and enzyme-linked immunosorbent assay (ELISA) were conducted on CD18 and S2-013 human pancreatic cancer cells treated with apigenin (0-50 μM) in normoxic and hypoxic conditions to evaluate HIF-1α, GLUT-1, and VEGF mRNA and protein expression and secretion.
  
  
  RESULTS
  GLUT-1 expression was significantly increased in pancreatic adenocarcinoma samples versus adjacent controls (P < 0.001). Hypoxic conditions induced HIF-1α, GLUT-1, and VEGF protein expression in both CD18 and S2-013 pancreatic cancer cells. Apigenin (50 μM) blocked hypoxia induced up-regulation of all three proteins in both cell lines. Apigenin also impeded hypoxia-mediated induction of GLUT-1 and VEGF mRNA in both cell lines (P < 0.05).
  
  
  CONCLUSIONS
  Apigenin inhibits HIF-1α, GLUT-1, and VEGF mRNA and protein expression in pancreatic cancer cells in both normoxic and hypoxic conditions. This may account for the mechanism of apigenin's anti-proliferative and anti-angiogenic effects and further supports the potential of apigenin as a future chemopreventive agent for pancreatic cancer.
authors.affiliation: Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Laleh G
authors.initials: LG
authors.lastname: Melstrom
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Salabat
authors.forename: Xian-Zhong
authors.initials: XZ
authors.lastname: Ding
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Strouch
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Grippo
authors.forename: Salida
authors.initials: S
authors.lastname: Mirzoeva
authors.forename: Jill C
authors.initials: JC
authors.lastname: Pelling
authors.forename: David J
authors.initials: DJ
authors.lastname: Bentrem
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D047310:Apigenin / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D000600:Amino Acids, Dicarboxylic; D004791:Enzyme Inhibitors; D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D047310:Apigenin; C040947:oxalylglycine