Androgen receptor signaling regulates growth of glioblastoma multiforme in men

Abstract

Although glioblastoma multiforme (GBM) is the most malignant primary human brain cancer with surprisingly high incidence rate in adult men than in women, the exact mechanism underlying this pronounced epidemiology is unclear. Here, we showed significant upregulated androgen receptor (AR) expression in the GBM tissue compared to the periphery normal brain tissue in patients. An expression of AR was further detected in all eight examined human GBM cell lines. To figure out whether AR signaling may play a role in GBM, we used high AR-expressing U87-MG GBM line for further study. We found that activation of transforming growth factor β (TGFβ) receptor signaling by TGFβ1 in GBM significantly inhibited cell growth and increased apoptosis. Moreover, application of active AR ligand 5α-dihydrotestosterone (DHT) significantly decreased the effect of TGFβ1 on GBM growth and apoptosis, suggesting that AR signaling pathway may contradict the effect of TGFβ receptor signaling in GBM. However, neither total protein nor the phosphorylated protein of SMAD3, a major TGFβ receptor signaling downstream effector in GBM, was affected by DHT, suggesting that AR activation may not affect the SMAD3 protein production or phosphorylation of TGFβ receptor and SMAD3. Finally, immunoprecipitation followed by immunoblot confirmed binding of pAR to pSMAD3, which may prevent the DNA binding of pSMAD3 and subsequently prevent its effect on cell growth in GBM. Taken together, our study suggests that AR signaling may promote tumorigenesis of GBM in adult men by inhibiting TGFβ receptor signaling.