The anti-tumor effect of androgen receptor antagonist on glioblastoma may result, at least partially, through attenuation of CDK4 and CDC14a expression

Background: Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults. We have recently demonstrated that genetic silencing and pharmacological inhibition of androgen receptor (AR) in GBM cell lines induce GBM cell death. Furthermore, enzalutamide (AR antagonist) given orally to nude mice bearing subcutaneous human glioma xenografts resulted in a 72% reduction in tumor volume (p=0.0027). This point to the important role of AR in GBM survival and render a potential therapeutic target for this devastating disease. Material and Methods: To elucidate the mechanistic role played by AR in GBM, three GBM cell lines (U87MG, A172, and T98G) were treated with either dihydrotestosterone (DHT) or with elevation concentrations of AR antagonist. Additionally, the cells were transfected with siRNA against AR to knock down its expression. Total RNA was extracted from the various study groups and relevant controls and were subjected to nanostring pancancer pathway array. Gene expression profile of the untreated cells was compared to the manipulated GBM cells. Results: Analysis of the array results revealed that either pharmacological inhibition of AR as well as genetic silencing of the receptor in GBM cell lines reduced the expression of CDK4 and CDC14a; both are involved in cell cycle progression. These results were further validated by qPCR. Analysis of several datasets including the TCGA, using Oncomine™ software revealed that these genes are significantly amplified in GBM and were shown before to be involved in GBM cell cycle progression. Conclusion: This study suggest that the antitumor effect of androgen receptor antagonist on GBM may result, at least partially, through attenuation of CDK4 and CDC14a expression. Additional research is needed to elucidate the mechanism of action of AR in GBM and to clarify the involvement of CDK4 and CDC14a in AR induced cell cycle progression.