Glioblastomas (GBM) are the most frequent and aggressive human brain tumors due to their high capacity to migrate and invade normal brain tissue. Epidemiological data report that GBM occur in a greater proportion in men than in women (3:2), suggesting the participation of sex hormones in the development of these tumors. It has been reported an increase in testosterone (T) levels in patients with GBM. In addition, androgen receptor (AR) is overexpressed in human GBM, and genetic silencing of AR, and its pharmacological inhibition, induce GBM cell death in vivo and in vitro. However, the role of T in proliferation, migration and invasion in human GBM cell lines has not been evaluated. We observed that T increased the number of U87, U251, and D54 cells derived from human GBM due to an increase in cell proliferation. This induction was blocked with flutamide, an antagonist of AR. T also induced migration and invasion of GBM cells that flutamide partially blocked. These data suggest that T through AR contributes to the progression of GBM by promoting proliferation, migration, and invasion.

Introduction Glioblastomas (GBM) are the most frequent and aggressive human brain tumors due to their high capacity to migrate, invade healthy brain tissue, and resist anticancer therapies. It has been reported that testosterone (T) levels are higher in patients with GBM than in healthy controls. It has also been dem{}onstrated that T induces proliferation, migration, and invasion of human GBM cell lines. T is mainly metabolized to 5α-dihydrotestosterone (DHT) by the enzyme 5α-reductase (5αR), but the role of this metabolite in GBM cells is unknown. Methods The expression of 5αR isoenzymes and AR in biopsies of GBMs was determined by the analysis of TCGA. U87 and U251 GBM cell lines were grown in supplemented DMEM. For evaluating the expression of AR in U251 and U87 cells, a RT-qPCR was performed. The cells were treated with T, DHT, finasteride (FIN), dutasteride (D), and the combined treatments, FIN+T and D+T or vehicle. After treatments, the viability was quantified by the trypan blue exclusion assay, the proliferation was evaluated by BrdU incorporation, and migration and invasion were analyzed by the scratch-wound and the transwell assays, respectively. Results In a set of glioma biopsies from TCGA, we observed that SRD5A2 (5αR2) expression was higher in GBM and in low-grade gliomas than in normal brain tissue. We observed that DHT and T increased proliferation, migration, and invasion of human GBM cell lines: U87 and U251. F and D, drugs that inhibit 5αR activity, blocked the effects of T on GBM cells. Discussion These data suggest that T induces human GBM progression through its conversion into DHT. These results can be related to the chemical structure of DHT, which increases its affinity for AR and decreases five times the rate of dissociation compared to T. Also, it is possible that DHT mediates the effects of T on cell human GBM cells motility by changing the expression of genes involved in tumor infiltration.

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