title: 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 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 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 TMZ‑resistant 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 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 ERβ knockdown or activation of the phosphatidylinositol‑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 ERβ agonists may become a feasible therapy option to overcome chemoresistance to TMZ.
authors.affiliation: School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Liu
authors.affiliation: China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China.
authors.forename: Libo
authors.initials: L
authors.lastname: Wang
authors.affiliation: China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Jilin Medical College, Jilin, Jilin 132013, P.R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Ling
authors.affiliation: Department of Vascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China.
authors.forename: Hongfei
authors.initials: H
authors.lastname: Wang
authors.affiliation: MOE Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering and School of Life Sciences, Fudan University, Shanghai 200433, P.R. China.
authors.forename: Shilin
authors.initials: S
authors.lastname: Li
authors.affiliation: MOE Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering and School of Life Sciences, Fudan University, Shanghai 200433, P.R. China.
authors.forename: Liming
authors.initials: L
authors.lastname: Li
authors.affiliation: MOE Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering and School of Life Sciences, Fudan University, Shanghai 200433, P.R. China.
authors.forename: Shuping
authors.initials: S
authors.lastname: Yang
authors.affiliation: MOE Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering and School of Life Sciences, Fudan University, Shanghai 200433, P.R. China.
authors.forename: Mingying
authors.initials: M
authors.lastname: Xia
authors.affiliation: School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Jing
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D044950:Flavanones / Q000494:pharmacology*; D005910:Glioma / Q000473:pathology; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D047629:Estrogen Receptor beta; D044950:Flavanones; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D000077204:Temozolomide; C083152:liquiritigenin