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

摘要

Glioma is the most common primary brain tumor among adults. Temozolomide (TMZ) is widely used as the first-line postsurgical drug for malignant glioma. However, the therapeutic efficacy of TMZ remains ineffective as inherited or acquired drug resistance is frequently observed. Estrogen receptor beta (ER beta) has emerged as a tumor suppressor and a key regulator of signal transduction in glioma cells. However, little is known about the role of ER beta in regulating the chemotherapeutic response to TMZ. In the current study, the TMZ-resistant U138 glioma cells were treated with the novel ER beta agonist liquiritigenin (Liq). It was observed that Liq significantly enhanced ER beta expression and sensitized glioma cells to TMZ-induced 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 TMZ-induced cytotoxicity. In addition, it was demonstrated that ER beta knockdown or activation of the phosphatidylinosito1-4,5-bisphosphate 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway by insulin-like 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 ER beta agonists may become a feasible therapy option to overcome chemoresistance to TMZ.