Chelation of iron enhances invasion of glioblastoma cells Free

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Diffusely infiltrating malignant cells, one of the hallmarks of glioblastoma multiforme (GBM, WHO IV), cannot efficiently be reached by surgical resection, radio- and chemotherapy. The prognosis for patients affected with GBM is poor. Understanding the mechanisms of the invasive behavior will contribute to improved treatment. Previous results of our group pointed towards the involvement of the iron pathway in the invasiveness of rat glioma cells.

In this study we examined the effect of the iron chelator desferrioxamine (DFO). Intracellular iron depletion in human GBM-cell lines DBTRG05MG and U373MG was achieved by application of DFO. Invasion of cells was examined by Transwell-infiltration assays. Expression of invasion associated factors was analyzed with Western Blot and Fluorescence Activated Cell Sorting.

We detected induction of GBM invasion after treatment of cells with 50 µM DFO. This was accompanied by an induction of expression of urokinase plasminogen activator receptor (uPAR) and matrix metalloproteinase type 2 playing a major role in degradation of extracellular matrix and GBM-invasion. Inhibition with topotecan demonstrated that hypoxia inducible factor 1 alpha was involved in DFO-induced uPAR expression. Inhibition of uPAR with siRNA resulted in reduced DFO-mediated GBM-invasion.

Our results hint towards a problem of an anti-proliferative therapy with iron chelators in invasive tumors such as GBM. The anti-proliferative effect of iron depletion comes at the cost of enhanced invasion.