Glioblastomas (GBMs) are the most frequent and malignant brain tumors in adults. Glucocorticoids (GCs) are routinely used in the treatment of GBMs for their capacity to reduce the tumor-associated edema. Few in vitro studies have suggested that GCs inhibit the migration and invasion of GBM cells through the induction of MAPK phosphatase 1 (MKP-1). Macrophage migration inhibitory factor (MIF), an endogenous GC antagonist is up-regulated in GBMs. Recently, MIF has been involved in tumor growth and migration/invasion and specific MIF inhibitors have been developed on their capacity to block its enzymatic tautomerase activity site. In this study, we characterized several glioma cell lines for their MIF production. U373 MG cells were selected for their very low endogenous levels of MIF. We showed that dexamethasone inhibits the migration and invasion of U373 MG cells, through a glucocorticoid receptor (GR)-dependent inhibition of the ERK1/2 MAPK pathway. Oppositely, we found that exogenous MIF increases U373 MG migration and invasion through the stimulation of the ERK1/2 MAP kinase pathway and that this activation is CD74 independent. Finally, we used the Hs 683 glioma cells that are resistant to GCs and produce high levels of endogenous MIF, and showed that the specific MIF inhibitor ISO-1 could restore dexamethasone sensitivity in these cells. Collectively, our results indicate an intricate pathway between MIF expression and GC resistance. They suggest that MIF inhibitors could increase the response of GBMs to corticotherapy.
Glioblastomas (GBMs)3 are the most frequent primitive cerebral tumor in adults. These highly invasive cancers are prone to infiltrate the surrounding brain parenchyma at considerable distance from the main tumor mass (1). This unavoidably leads to local recurrence and death despite combined surgery, irradiation, and chemotherapy (2, 3).Glucocorticoids (GCs) are routinely used in the treatment of GBMs as they dramatically reduce the tumor-associated edema. There is growing evidence that GCs also inhibit glioma cell proliferation in vitro and tumor growth in vivo (reviewed in Ref. 4). The capacity of GCs to alter migration and invasion in gliomas has received less attention (5, 6). However, dexamethasone was reported to inhibit cell migration and invasion by opposing epidermal growth factor-induced enhancement of urokinase-type plasminogen activator and urokinase-type plasminogen activator receptor in squamous cell carcinoma cells (7), by modulating matrix metalloproteinase activity in vascular smooth muscle cells (8), by enhancing ␣11 integrin expression in human gastric carcinoma cells (9), and by altering the cytoskeleton of human neurobastoma cells (10). In gliomas, the exact mechanisms of this inhibition are yet largely unknown. Bauman et al. (5) showed that dexamethasone inhibits the migration/ invasion of several glioma cell lines (C6, U251, U373, and A172) and that it enhances the inhibition induced by irradiation. Lin et al. (6) recently showed that dexamethasone decreases matrix me...