Liu Yang, Huang Liang, Guan Xin, Li Hongyan, Zhang Qi-Qi, Han Chao, Wang Ya-Jun, Wang Cui, Zhang Yejun, Qu Chao, Liu Jing, Zou Wei
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.
College of Life Science, Liaoning Normal University, Dalian 116081, China.
Steroids. 2016 Jul;111:127-133. doi: 10.1016/j.steroids.2016.02.009. Epub 2016 Feb 18.
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.
尽管越来越多的证据证实，辅助性他莫昔芬（TAM）治疗能够使胶质母细胞瘤细胞对放疗敏感并抑制其增殖，但TAM并非适用于所有类型的胶质母细胞瘤细胞；此外，长期使用TAM可能导致TAM耐药。因此，了解TAM耐药的潜在分子机制对于改善TAM临床治疗以及胶质母细胞瘤患者的生活质量是必要的。在本研究中，检测了ER-α36对胶质母细胞瘤细胞中TAM耐药的意义。首先，对两种胶质母细胞瘤细胞系U87-MG和U251中的ER-α36表达进行分析，结果显示ER-α36通过小窝蛋白-1锚定在这些细胞的细胞质膜上。随后研究TAM诱导U87-MG细胞生长抑制机制的实验表明，TAM通过下调Survivin表达和上调Caspase-3表达诱导细胞凋亡来发挥作用。此外，TAM还使细胞周期停滞在S期。然而，当用ER-α36特异性激动剂IC162预处理U87-MG细胞时，这抵消了TAM诱导的细胞生长抑制。这与RNAi介导的ER-α36缺失的效果形成对比，后者增强了TAM诱导的细胞生长抑制。这些发现表明，对TAM的耐药涉及ER-α36，其可能作为TAM诱导的胶质母细胞瘤细胞生长抑制的负调节因子。这些发现为胶质母细胞瘤治疗期间TAM耐药的基础提供了新的见解，并且正在进行进一步研究以揭示更多与ER-α36介导的TAM耐药相关的具体分子机制。
