Glucose-dependent GPER1 expression modulates tamoxifen-induced IGFBP-1 accumulation
Glucose-dependent GPER1 expression modulates tamoxifen-induced IGFBP-1 accumulation
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DOI：
10.1530/jme-18-0253
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发表时间：
2019-08-01
影响因子：
3.5
通讯作者：
Houston, Kevin D.
中科院分区：
文献类型：
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作者：
Zheng, Yan;Houston, Kevin D.
G蛋白偶联雌激素受体1（GPER 1）是一种七跨膜受体，介导雌激素刺激的快速细胞信号传导事件。虽然GPER 1在调节E2-应答组织和癌症中的作用已得到充分证实，但调节GPER 1表达的分子机制目前尚未明确。最近确定的GPER 1依赖性机制，他莫昔芬在乳腺癌细胞中的作用，强调了确定机制，调节GPER 1在这种细胞类型的表达的重要性。我们假设乳腺癌细胞中的GPER 1表达对[D-葡萄糖]敏感，并提供了当细胞在低[D-葡萄糖]中培养时GPER 1表达增加的数据。为了确定观察到的GPER 1的蓄积是否是AMP活化蛋白激酶（AMPK）依赖性的，进行AMPK的小分子刺激或抑制。AMPK抑制降低了在低[D-葡萄糖]中生长的细胞中GPER 1的积累，而AMPK激活化合物AICAR增加了在高[D-葡萄糖]培养基中生长的细胞中GPER 1的积累。此外，用表达组成型活性AMPK的质粒转染细胞导致GPER 1积累增加。为了确定[D-葡萄糖]依赖性GPER 1积累是否改变了乳腺癌细胞对他莫昔芬的反应，将在[D-葡萄糖]减少的情况下生长的细胞与他莫昔芬共处理，并测量IGFBP-1转录。这些实验的结果表明，D-葡萄糖剥夺增加了GPER 1介导的和他莫昔芬诱导的IGFBP-1转录，表明[D-葡萄糖]可能增加乳腺癌细胞对他莫昔芬的敏感性。总之，这些结果确定了一个以前未知的机制，调节GPER 1的表达，修改一个方面他莫昔芬在乳腺癌细胞中的作用。
G protein-coupled estrogen receptor 1 (GPER1) is a seven-transmembrane receptor that mediates rapid cell signaling events stimulated by estrogens. While the role that GPER1 has in the modulation of E2-responsive tissues and cancers is well documented, the molecular mechanisms that regulate GPER1 expression are currently not well defined. The recently identified GPER1-dependent mechanism of tamoxifen action in breast cancer cells underscores the importance of identifying mechanisms that regulate GPER1 expression in this cell type. We hypothesized that GPER1 expression in breast cancer cells is sensitive to [D-glucose] and provide data showing increased GPER1 expression when cells were cultured in low [D-glucose]. To determine if the observed accumulation of GPER1 was AMP-activated protein kinase (AMPK)-dependent, small molecule stimulation or inhibition of AMPK was performed. AMPK inhibition decreased GPER1 accumulation in cells grown in low [D-glucose] while the AMPK-activating compound AICAR increased GPER1 accumulation in cells grown in high [D-glucose] media. Additionally, transfection of cells with a plasmid expressing constitutively active AMPK resulted in increased GPER1 accumulation. To determine if [D-glucose]-dependent GPER1 accumulation altered breast cancer cell response to tamoxifen, cells grown in the presence of decreasing [D-glucose] were co-treated with tamoxifen and IGFBP-1 transcription was measured. The results from these experiments reveal that D-glucose deprivation increased GPER1-mediated and tamoxifen-induced IGFBP-1 transcription suggesting that [D-glucose] may increase breast cancer cell sensitivity to tamoxifen. Taken together, these results identify a previously unknown mechanism that regulates GPER1 expression that modifies one aspect tamoxifen action in breast cancer cells.