Androgen receptor: a potential therapeutic target for glioblastoma
Autor: | Bracha Zelikovitch, Hanna Charbit, Stav Rabani, Tamar Canello, Anat Mordechai, Haim Ovadia, Yakov Fellig, Tal Shahar, Iris Lavon, Alexander Lossos, Nomi Zalcman |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Programmed cell death androgen receptor (AR) Biology AR variant 7 (AR3) 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo Glioma medicine AR antagonist Gene silencing Enzalutamide Receptor medicine.disease nervous system diseases Androgen receptor gliomas 030104 developmental biology Oncology chemistry Cell culture 030220 oncology & carcinogenesis Cancer research glioblastoma (GBM) Research Paper |
Zdroj: | Oncotarget |
ISSN: | 1949-2553 |
Popis: | 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. |
Databáze: | OpenAIRE |
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