Abstract
The median survival time of patients with glioblastoma is still poor (14.6 month), partly due to a lack of effective treatment.We have observed that androgen receptor (AR) is amplified in glioblastomas at the DNA, RNA and protein levels. The AR gene was amplified in 27% of glioblastoma specimens from men (n=22) and of 38.2% from women (n=21). AR-RNA was overexpressed (>2.5 fold) in 93% (n=30), and AR-protein was induced (>two fold) in 56% of the glioblastomas samples (n=16). Thirty percent of the glioblastomas (n=21) also expressed a constitutively active AR-splice-variant (AR-V7/AR3) lacking the Ligand-Binding-Domain. Following these findings, we examined the effect of pharmacological inhibition of androgen receptor in vitro and in vivo, as well as of genetic silencing of the receptor in glioblastoma cell lines. AR antagonists, induced concentration-dependent death in three glioblastoma cell lines, as well as in two glioma initiating cell lines. Silencing of AR expression by siRNA induced cell death in the three tested glioblastoma cell lines. Enzalutamide given orally to nude mice bearing subcutaneous human glioma xenografts resulted in a 72% reduction in tumor volume (p=0.0027).The presence of AR-V7/AR3 in glioblastoma, together with the present data showing that genetic silencing of the full length AR in cell lines and pharmacological inhibition of AR, induce GBM cell death in vivo and in vitro, point to the important role of AR in GBM survival and render a potential therapeutic target for this devastating disease.
Highlights
Glioblastoma (GBM) is the most common and the most aggressive primary brain tumor, with a very poor prognosis
We examined the effect of pharmacological inhibition of androgen receptor in vitro and in vivo, as well as of genetic silencing of the receptor in glioblastoma cell lines
Enzalutamide given orally to nude mice bearing subcutaneous human glioma xenografts resulted in a 72% reduction in tumor volume (p=0.0027)
Summary
Glioblastoma (GBM) is the most common and the most aggressive primary brain tumor, with a very poor prognosis. In the presence of ligand, the ligandbinding domain is released from heat shock protein and AR is translocated into the nucleus, where it binds to the androgen-response-element in the promoter and stimulates transcription of androgen- responsive genes [7] It has been shown in prostate and breast cancers that activation of AR can be achieved by ligand-independent signaling through crosstalk with other molecular signaling pathways, as a consequence of activation of the downstream PI3K/ AKT/mTOR. Such pathways include receptor tyrosine kinases (RTKs), such as the insulin-like growth factor keratinocyte growth factor (KGF), EGFR and Human Epidermal Growth Factor Receptor 2 (HER2) [8,9,10,11]. These AR-independent pathways can promote cancer cell survival and growth (reviewed in [7]) and appear to be a major androgen-independent driver of AR-regulated gene expression in castration-resistant prostate cancer
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