ER-α36, a novel variant of ERα, is involved in the regulation of Tamoxifen-sensitivity of glioblastoma cells

Steroids. 2016 Jul:111:127-133. doi: 10.1016/j.steroids.2016.02.009. Epub 2016 Feb 18.

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.

Keywords: ER-α36; Glioblastoma cells; Sensitivity; Tamoxifen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Flow Cytometry
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Humans
  • Microscopy, Confocal
  • Reverse Transcriptase Polymerase Chain Reaction
  • S Phase / drug effects
  • S Phase / genetics
  • Tamoxifen / pharmacology*

Substances

  • Estrogen Receptor alpha
  • estrogen receptor alpha 36, human
  • Tamoxifen