title: FoxO3a induces temozolomide resistance in glioblastoma cells via the regulation of β-catenin nuclear accumulation.
abstract: Glioblastoma multiforme (GBM), the most common malignant brain tumor, is currently treated with temozolomide (TMZ), but GBM often exhibits resistance to TMZ. Although several mechanisms underlying GBM resistance to TMZ have been identified, these mechanisms are yet to fully explain how GBM gains resistance to TMZ. Our previous work has shown that FoxO3a, a member of the FoxO subfamily of transcription factors, promotes glioma cell proliferation and invasion. In this study, we sought to determine whether FoxO3a participates in TMZ resistance in GBM cells. Parental cell lines (also designated as sensitive cell lines) U87-MG and U251-MG, as well as the corresponding resistant cell lines U87-TR and U251-TR (generated by repeated TMZ treatments), were subjected to western blot analysis. Our results showed that the resistant cells (both U87-TRand U251-TR) exhibited higher levels of FoxO3a and β-catenin relative to their corresponding sensitive counterparts. Depletion of FoxO3a in the resistant cells enhanced the cytotoxic effect of TMZ. Further investigation showed that FoxO3a depletion did not affect the total protein level of β-catenin, but otherwise markedly reduced the nuclear β-catenin level. Taken together, these findings strongly support that FoxO3a renders GBM cells resistant to TMZ treatment, at least in part, through the regulation of β-catenin nuclear accumulation.
authors.affiliation: Department of Immunology, School of Tropical and Laboratory Medicine, Hainan Medical University, Haikou, Hainan 571101, P.R. China.
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.affiliation: Medical Technology Institute of Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China.
authors.forename: Zhenhao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Immunology, School of Tropical and Laboratory Medicine, Hainan Medical University, Haikou, Hainan 571101, P.R. China.
authors.forename: Hua
authors.initials: H
authors.lastname: Pei
authors.affiliation: Department of Immunology, School of Tropical and Laboratory Medicine, Hainan Medical University, Haikou, Hainan 571101, P.R. China.
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Immunology, School of Tropical and Laboratory Medicine, Hainan Medical University, Haikou, Hainan 571101, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: Key Laboratory of Tropical Biomedicine, and Faculty of Tropical Medicine and Laboratory Medicine, Hainan Medical University, Haikou, Hainan 571101, P.R. China.
authors.forename: Qianfeng
authors.initials: Q
authors.lastname: Xia
mesh_terms: D017209:Apoptosis; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D000077204:Temozolomide; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051176:beta Catenin; D003606:Dacarbazine; D000077204:Temozolomide