Activation of a putative membrane androgen receptor increases the efficacy of the chemotherapeutic agent, temozolomide, in a human glioblastoma cell line

Glioblastoma Multiforme (GBM) is a form of brain cancer with very poor prognosis such that the life expectancy of a person with this disease is about one year after diagnosis. Moreover, current treatment regimens are only able to extend the life span by mere months. Based on recent studies from our lab that identified a putative membrane androgen receptor (mAR), which when activated is capable of promoting cell death, we investigated whether exploitation of this receptor could increase the efficacy of current chemotherapeutic agents to combat this deadly and invariably lethal cancer. Using the human glioblastoma cell lines, A172 and T98G, our studies have shown that activation of the mAR (using testosterone or dihydrotestosterone conjugated to bovine serum albumin) not only sensitized the glioblastoma cells to temozolomide (TMZ), the current standard chemotherapeutic agent for GBM, but also suppressed the phosphorylation of Akt, a known survival-promoting factor. Further, in T98G cells that express high levels of O6-methylguanine DNA methyltransferase (MGMT), a DNA repair protein, activation of the mAR suppressed the expression of MGMT. Our data also suggest that these mechanisms may not be mutually exclusive such that inhibition of Akt phosphorylation in and of itself led to a reduction in MGMT expression. Collectively, our data support the targeting of a putative membrane androgen receptor as complementary treatment for glioblastoma.