Estrogen receptor variant ER-α36 promotes tamoxifen agonist activity in glioblastoma cells
Estrogen receptor variant ER-α36 promotes tamoxifen agonist activity in glioblastoma cells
复制标题
DOI：
10.1111/cas.13868
复制
发表时间：
2019-01-01
期刊：
影响因子：
5.7
通讯作者：
Zou, Wei
中科院分区：
文献类型：
--
作者：
Qu, Chao;Ma, Jingyun;Zou, Wei
胶质母细胞瘤（GBM）是一种高度浸润性和恶性的原发性脑肿瘤。尽管有积极的治疗，GBM患者的预后很差，中位生存期约为1年。他莫昔芬（TAM）是一种选择性雌激素受体调节剂（SERM），多年来一直用于治疗GBM。ER-α 36是雌激素受体-α 66（ER-α 66）的一种新变体，并且可以在不同的癌细胞中通过雌激素或抗雌激素信号传导介导细胞增殖。以前，我们发现ER-α 36在GBM中高度表达，并参与胶质母细胞瘤细胞对他莫昔芬的敏感性。然而，负责的分子机制还没有很好地建立。在这里，我们发现ER-α 36在胶质母细胞瘤标本中高度表达。我们进一步发现，ER-α 36敲低增加了胶质母细胞瘤U87细胞对TAM的敏感性，并减少了这些细胞中的自噬。然而，ER-α 36过表达降低TAM敏感性并诱导自噬。我们还通过在含TAM的培养基中长期培养建立了TAM抗性胶质母细胞瘤U251细胞，并发现TAM抗性细胞显示ER-α 36 mRNA表达增加6倍和基础自噬升高。这些TAM抗性细胞中的ER-α 36敲低恢复了TAM敏感性。此外，我们在集成的微流体装置中概括了生理相关的肿瘤微环境，并用TAM梯度处理U87细胞。我们发现ER-α 36的表达与三维微环境中的自噬蛋白P62一致。总之，这些结果表明ER-α 36可能通过调节自噬而导致胶质母细胞瘤细胞中的他莫昔芬抗性。
Glioblastoma (GBM) is a highly infiltrative and malignant primary brain tumor. Despite aggressive therapy, patients with GBM have a dismal prognosis with median survival of approximately 1 year. Tamoxifen (TAM), a selective estrogen receptor modulator (SERM), has been used to treat GBM for many years. ER-alpha 36 is a novel variant of estrogen receptor-alpha66 (ER-alpha 66) and can mediate cell proliferation through estrogen or anti-estrogen signaling in different cancer cells. Previously, we found that ER-alpha 36 was highly expressed in GBM and was involved in the tamoxifen sensitivity of glioblastoma cells. However, the molecular mechanism responsible has not been well established. Here, we found that ER-alpha 36 is highly expressed in glioblastoma specimens. We further found that ER-alpha 36 knockdown increased sensitivity of glioblastoma U87 cells to TAM and decreased autophagy in these cells. However, ER-alpha 36 overexpression decreased TAM sensitivity and induced autophagy. We also established TAM-resistant glioblastoma U251 cells by a long-term culture in TAM-containing medium and found that TAM-resistant cells showed a six-fold increase of ER-alpha 36 mRNA expression and elevated basal autophagy. ER-alpha 36 knockdown in these TAM-resistant cells restored TAM sensitivity. In addition, we recapitulated the physiologically relevant tumor microenvironment in an integrated microfluidic device, and U87 cells were treated with a gradient of TAM. We found that ER-alpha 36 expression is consistent with autophagy protein P62 in a three-dimensional microenvironment. In summary, these results indicate that ER-alpha 36 contributes to tamoxifen resistance in glioblastoma cells presumably through regulation of autophagy.