Estrogen receptor β agonist enhances temozolomide sensitivity of glioma cells by inhibiting PI3K/AKT/mTOR pathway

Abstract

Glioma is the most common primary brain tumor among adults. Temozolomide (TMZ) is widely used as the firstline postsurgical drug for malignant glioma. However, the therapeutic efficacy of TMZ remains ineffective as inherited or acquired drug resistance is frequently observed. Estrogen receptor β (ERβ) has emerged as a tumor suppressor and a key regulator of signal transduction in glioma cells. However, little is known about the role of ERβ in regulating the chemotherapeutic response to TMZ. In the current study, the TMZresistant U138 glioma cells were treated with the novel ERβ agonist liquiritigenin (Liq). It was observed that Liq significantly enhanced ERβ expression and sensitized glioma cells to TMZinduced proliferation inhibition. As a potential mechanism, it was noted that Liq treatment significantly inhibited the activity of the PI3K/AKT/mTOR pathway, which played a protective role against the TMZinduced cytotoxicity. In addition, it was demonstrated that ERβ knockdown or activation of the phosphatidylinositol4,5bisphosphate 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway by insulinlike growth factor 1 both eradicated the function of Liq. These results suggest that Liq treatment enhances glioma cell susceptibility to TMZ by inhibiting the PI3K/AKT/mTOR pathway. As hyperactivation of the PI3K/AKT/mTOR pathway is frequently observed in gliomas, the combined use of ERβ agonists may become a feasible therapy option to overcome chemoresistance to TMZ.