Testosterone Promotes Glioblastoma Cell Proliferation, Migration, and Invasion Through Androgen Receptor Activation

Abstract

Glioblastomas (GBM) are the most frequent and aggressive human brain tumors due to their high capacity to migrate and invade normal brain tissue. Epidemiological data report that GBM occur in a greater proportion in men than in women (3:2), suggesting the participation of sex hormones in the development of these tumors. It has been reported an increase in testosterone (T) levels in patients with GBM. In addition, androgen receptor (AR) is overexpressed in human GBM, and genetic silencing of AR, and its pharmacological inhibition, induce GBM cell death in vivo and in vitro. However, the role of T in proliferation, migration and invasion in human GBM cell lines has not been evaluated. We observed that T increased the number of U87, U251, and D54 cells derived from human GBM due to an increase in cell proliferation. This induction was blocked with flutamide, an antagonist of AR. T also induced migration and invasion of GBM cells that flutamide partially blocked. These data suggest that T through AR contributes to the progression of GBM by promoting proliferation, migration, and invasion.

The Role of Translocator Protein TSPO in Hallmarks of Glioblastoma

“…Selective estrogen receptor modulators such as estradiol and 2-methoxyestradiol are shown to inhibit the proliferation of gliomas and induce cell death in experimental in vitro settings [ 109 ]. In line with these findings, an increased level of testosterone has been reported in patients with GBM [ 113 ]. In addition, androgen receptors are overexpressed in human GBM, and the genetic silencing of androgen receptors as well as their pharmacological inhibition, induce GBM cell death in vivo and in vitro [ 114 , 115 , 116 ].…”

“…In addition, androgen receptors are overexpressed in human GBM, and the genetic silencing of androgen receptors as well as their pharmacological inhibition, induce GBM cell death in vivo and in vitro [ 114 , 115 , 116 ]. Furthermore, the proliferation of GBM-derived cells was increased by testosterone, an effect that was antagonized by the androgen receptor antagonist flutamide [ 113 ]. The effects of the hormonal agonists and antagonists can either depend on classical steroid hormone receptor signaling or on alternative pathways [ 109 ].…”

Astrocytoma: A Hormone-Sensitive Tumor?

“…Bunevicius and colleagues [84] suggested a greater prenatal testosterone and lower prenatal estrogen exposure in brain tumor patients [84,85]. Moreover, testosterone (100 nM) and DHT (10 nM) exposed U87, U251 and D54 GBM cells displayed enhanced proliferation, migration and invasion [86,87]. In rats xenografted with GBM, experimental castration reduced the incidence of tumor development and increased the time between implantation and death [88].…”

The Role of NK Cells and Innate Lymphoid Cells in Brain Cancer

“…Interestingly, the primary male sex hormone testosterone, influenced ILC2 numbers and function and promoted and sustained a non-pathogenic TH2 myelin-specific response in EAE. These results suggest sexual dimorphism in ILC2 numbers or function could influence ILC2 brain tumor surveillance in addition to GBM invasiveness ( 105 , 106 ). The protective role of activated ILC2s that observed during CNS injury, EAE, and restriction of brain metastases, suggests a potential role for activated meningeal ILC2s in suppressing brain tumor progression by enhancing CTL activity in response to elevated levels of IL-33 that are observed in brain cancers, such as glioma ( 107 ).…”