title: Glucose requirement for hypoxic accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha).
abstract: Hypoxia-inducible factor-1alpha (HIF-1alpha) is both a potential endogenous marker of tumor hypoxia and therapeutic target, and elevated HIF-1alpha protein levels have been shown to be associated with increased hypoxic radiation resistance in FaDu human pharyngeal carcinoma cells in vitro. Here, we found that in FaDu xenografts, no significant HIF-1alpha protein accumulation was detectable by either flow cytometry or Western blot, despite the presence of hypoxic (pimonidazole-positive, radiation resistant) cells. To investigate the effect of different tumor microenvironment conditions on hypoxic HIF-1alpha accumulation, we performed in vitro hypoxia experiments (0.1% O2, 24 h) with manipulation of pH (7.4 vs. 6.7), glucose (0-5.5 mM) and serum (0 or 10%) availability in FaDu and HT 1080 human fibrosarcoma cells. Hypoxic induction of HIF-1alpha protein was strongly dependent on glucose availability and largely abolished at 0.55 mM glucose or less in both cell lines. This glucose effect was confirmed in a hypoxia-responsive-element (HRE)/enhanced-green-fluorescent-protein (EGFP) reporter assay in transfected HT 1080 cells and possibly explains a lack of HIF-1alpha protein in hypoxic tumor cells.
authors.affiliation: Department of Radiation Oncology, University of Würzburg, Josef-Schneider-Str. 11, 97080 Würzburg, Germany. vordermark_d@klinik.uni-wuerzburg.de
authors.forename: Dirk
authors.initials: D
authors.lastname: Vordermark
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Astrid
authors.initials: A
authors.lastname: Katzer
authors.forename: Tobias
authors.initials: T
authors.lastname: Bölling
authors.forename: Jochen
authors.initials: J
authors.lastname: Willner
authors.forename: Michael
authors.initials: M
authors.lastname: Flentje
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western; D002277:Carcinoma / Q000473:pathology*; D015687:Cell Hypoxia; D005354:Fibrosarcoma / Q000473:pathology*; D005434:Flow Cytometry; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D010610:Pharyngeal Neoplasms / Q000473:pathology*; D011836:Radiation Tolerance; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D015415:Biomarkers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D005947:Glucose