title: ER-α36, a novel variant of ERα, is involved in the regulation of Tamoxifen-sensitivity of glioblastoma cells.
abstract: Although accumulating evidence has confirmed that adjuvant Tamoxifen (TAM) treatment is able to sensitize glioblastoma cells to radiotherapy and inhibit their proliferation, TAM is not a suitable treatment for all types of glioblastoma cells; furthermore, long-term TAM usage may lead to TAM resistance. Therefore, understanding the underlying molecular mechanism of TAM resistance is necessary in order to improve TAM clinical therapy and the quality of life of patients suffering from glioblastomas. In this study, the significance of ER-α36 to TAM resistance in glioblastoma cells was examined. First, an analysis of ER-α36 expression in two glioblastoma cell lines U87-MG and U251, showed that ER-α36 was anchored to the cytoplasmic membrane of these cells via Caveolin-1. Subsequent experiments investigating the mechanism of TAM-induced inhibition of U87-MG cell growth showed that TAM exerts its effect by inducing apoptosis via a down-regulation of Survivin expression and an up-regulation of Caspase-3 expression. Furthermore, TAM also arrested the cell cycle at S-phase. However, when U87-MG cells were preconditioned with an ER-α36-specific agonist, IC162, this neutralized TAM-induced inhibition of cell growth. This contrasted with the effect of ER-α36 depletion by RNAi, which enhanced TAM-induced inhibition of cell growth. These findings suggest that resistance to TAM involves ER-α36, which probably acts as a negative regulator of TAM-induced inhibition of glioblastoma cell growth. These findings provide a novel insight into the basis of TAM resistance during glioblastoma therapy and a further study is underway to reveal more about the specific molecular mechanisms associated with ER-α36-mediated TAM resistance.
authors.affiliation: College of Life Science, Liaoning Normal University, Dalian 116081, China; State Key Laboratory of Genetic Engineering, College of Life Science, Fudan University, Shanghai 200433, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: College of Life Science, Liaoning Normal University, Dalian 116081, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Huang
authors.affiliation: College of Life Science, Liaoning Normal University, Dalian 116081, China; Regenerative Medicine Centre, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Guan
authors.affiliation: College of Life Science, Liaoning Normal University, Dalian 116081, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Li
authors.affiliation: College of Life Science, Liaoning Normal University, Dalian 116081, China.
authors.forename: Qi-Qi
authors.initials: QQ
authors.lastname: Zhang
authors.affiliation: Regenerative Medicine Centre, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Han
authors.affiliation: College of Life Science, Liaoning Normal University, Dalian 116081, China.
authors.forename: Ya-Jun
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian 116000, China.
authors.forename: Cui
authors.initials: C
authors.lastname: Wang
authors.affiliation: College of Life Science, Liaoning Normal University, Dalian 116081, China.
authors.forename: Yejun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: College of Life Science, Liaoning Normal University, Dalian 116081, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Qu
authors.affiliation: Regenerative Medicine Centre, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China. Electronic address: liujing.dlrmc@hotmail.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: College of Life Science, Liaoning Normal University, Dalian 116081, China. Electronic address: weizou60@hotmail.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Zou
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018613:Microscopy, Confocal; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase / Q000187:drug effects / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D047628:Estrogen Receptor alpha; C000601334:estrogen receptor alpha 36, human; D013629:Tamoxifen
keywords: ER-α36; Glioblastoma cells; Sensitivity; Tamoxifen