Involvement of Hif-1 in desferrioxamine-induced invasion of glioblastoma cells.
Glioblastoma multiforme are highly invasive brain tumors. Experimental approaches focus on unravelling the mechanisms of invasion, this being a major reason for the poor prognosis of these tumors. Our previous results hinted towards involvement of the iron metabolism in invasion. In this study, we examined the effect of iron depletion on the invasive phenotype of glioblastoma cells. Transwell Matrigel invasion assays were used to monitor iron-dependent invasion of human glioblastoma cell lines U373MG and DBTRG05MG. Intracellular iron concentrations were modulated by applying desferrioxamine (DFO) and ferric ammonium citrate (FAC). We detected enhanced invasion of glioblastoma cells upon DFO-induced iron depletion. Treatment of cells with FAC strongly inhibited invasion. DFO treatment resulted in hypoxia-inducible factor 1 (Hif-1)-mediated induction of urokinase plasminogen activator receptor and matrix metalloproteinase 2. Further, RNA interference-mediated repression of urokinase plasminogen activator receptor inhibited DFO-induced invasion. Our data demonstrate a direct effect of DFO on Hif-1 expression resulting in activation of factors associated with ECM degradation and invasion of glioma cells. These findings caution on utilization of DFO and other iron chelators in the treatment of tumors with invasive potential.
Elstner
Anja
A
Department of Neuropathology and Clinical Cooperation Unit Neuropathology, University Hospital Heidelberg and German Cancer Center (DKFZ), Im Neuenheimer Feld 220, 69120 Heidelberg, Germany.
Holtkamp
Nikola
N
von Deimling
Andreas
A
D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002469:Cell Separation; D003676:Deferoxamine / Q000494:pharmacology*; D005434:Flow Cytometry; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology*; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D014162:Transfection
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents; C524898:PLAUR protein, human; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D007501:Iron; D020778:Matrix Metalloproteinase 2; D003676:Deferoxamine