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

Liu, Yang; Huang, Liang; Guan, Xin; Li, Hongyan; Zhang, Qi-Qi; Han, Chao; Wang, Yajun; Wang, Cui; Zhang, Yejun; Qu, Chao; Liu, Jing; Zou, Wei

doi:10.1016/j.steroids.2016.02.009

Cited by 19 publications

(25 citation statements)

References 19 publications

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“…This study found that ER‐α36 is coexpressed with GFAP in ER‐negative specimens from glioma patients. In a previous study, we found that glioblastoma U87 and U251 cells lack 66‐kDa ER‐α (ER‐α66) expression but express ER‐α36 and mediated TAM resistance . Interestingly, TAM sensitivity depends on the level of ER‐α36 expression; U87 cells that express more ER‐α36 are less sensitive to TAM compared to U251 cells that express less ER‐α36.…”

Section: Discussionmentioning

confidence: 98%

“…TAM has been shown to inhibit glioma cell proliferation and induce apoptosis through activation of multiple upstream pathways in vitro . Our laboratory reported that ER‐α36 is involved in the regulation of tamoxifen sensitivity in glioblastoma cells, suggesting a possible role of ER‐α36 in TAM resistance …”

Section: Introductionmentioning

confidence: 90%

“…Glioblastoma U87 and U251 were obtained from ATCC (Manassas, VA, USA). Stable cell line (U87‐36KD) was established as described in our previous study . All cells were maintained in DMEM with 10% FBS at 37°C in 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…Concentration of total protein was determined by the Bradford method. Proteins were separated by SDS‐PAGE analyzed with western blot as described previously …”

Section: Methodsmentioning

confidence: 99%

“…ER‐α36 has a unique 27 amino acid domain to replace the last 138 amino acids encoded by exons 7 and 8 of ER‐α66. Different groups reported that ER‐α36 is expressed in human breast cancer, human bone tissue, glioma cells, hippocampus, and neuron‐like PC12 cells . Li et al found that ER‐α36 is involved in development of acquired TAM resistance by regulating the growth status switch in breast cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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Estrogen receptor variant ER‐α36 promotes tamoxifen agonist activity in glioblastoma cells

Zhang

et al. 2019

Cancer Science

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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‐α36 is a novel variant of estrogen receptor‐alpha66 (ER‐α66) and can mediate cell proliferation through estrogen or anti‐estrogen signaling in different cancer cells. Previously, we found that ER‐α36 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‐α36 is highly expressed in glioblastoma specimens. We further found that ER‐α36 knockdown increased sensitivity of glioblastoma U87 cells to TAM and decreased autophagy in these cells. However, ER‐α36 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‐α36 mRNA expression and elevated basal autophagy. ER‐α36 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‐α36 expression is consistent with autophagy protein P62 in a three‐dimensional microenvironment. In summary, these results indicate that ER‐α36 contributes to tamoxifen resistance in glioblastoma cells presumably through regulation of autophagy.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

“…Concentration of total protein was determined by the Bradford method. Proteins were separated by SDS‐PAGE analyzed with western blot as described previously …”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Estrogen receptor variant ER‐α36 promotes tamoxifen agonist activity in glioblastoma cells

Zhang

et al. 2019

Cancer Science

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Knockdown of ER‐α36 expression inhibits glioma proliferation, invasion and epithelial‐to‐mesenchymal transition

Zhao

Xiang

Yang

et al. 2021

The Anatomical Record

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Estrogen receptor-α36 (ER-α36), a subtype of the estrogen receptor, is reported to play roles in tumorigenesis and tamoxifen resistance in several tumors, especially breast cancer. However, the role of ER-α36 in glioma proliferation and invasion remains unknown. Here, we explored the function of ER-α36 in glioma cells, using U87 and U251 cell lines. We found that ER-α36 was upregulated in glioma tissues compared to adjacent nontumor tissues. In U87 and U251 glioma cell lines, inhibition of ER-α36 expression by shRNA suppressed cell proliferation and invasion. In addition, the expression of an epithelial marker, ZO-1, was upregulated while that of one mesenchymal marker, N-cadherin, was downregulated with ER-α36 knockdown.We also found that inhibition of ER-α36 inactivated both PI3K/AKT and MEK/ERK signals. Taken together, these data indicated that overexpression of ER-α36 is associated with glioma proliferation and progression but that inhibition of ER-α36 leads to suppressed invasion and the epithelial-tomesenchymal transition via PI3K/AKT and MEK/ERK pathway inactivation in glioma cells.

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Estrogen receptor variant ER‐α36 facilitates estrogen signaling via EGFR in glioblastoma

Wang

et al. 2022

Cell Biology International

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Glioblastoma (GBM) is a deadly and common primary brain tumor. Poor prognosis is linked to high proliferation and cell heterogeneity. Sex differences may play a role in patient outcome. Previous studies showed that ER‐α36, a variant of the estrogen receptor (ER), mediated non‐genomic estrogen signaling and is highly expressed in many ER‐negative malignant tumors. ER‐α36 also associates with epidermal growth factor receptor (EGFR). The primary purpose of this study is to investigate the cross talk between ER‐α36 and EGFR in estrogen‐mediated GBM cell proliferation. Here, we showed that ER‐α36 was highly expressed and confirmed that ER‐α36 co‐labels with EGFR in human GBM samples using immunohistochemical techniques. We also investigated the mechanisms of estrogen‐induced proliferation in ER‐α‐negative cell lines. We found that GBM cells showed varying responsive to mitogenic estrogen signaling which correlated with ER‐α36 expression, and knockdown of ER‐α36 diminished the response. Exposure to estrogen also caused upregulation of cyclin protein expression in vitro. We also found that low concentration of estrogen promoted SRC‐Y‐416 and inhibited SRC‐Y‐527 phosphorylation, corresponding with activated SRC signaling. Inhibiting SRC or EGFR abolished estrogen‐induced mitogenic signaling, including cyclin expression and MAPK phosphorylation. Cumulatively, our results demonstrate that ER‐α36 promotes non‐genomic estrogen signaling via the EGFR/SRC/MAPK pathway in GBM. This may be important for the treatment of ER‐α‐negative GBMs that retain high level of ER‐α36, since estrogen may be a viable therapeutic target for these patients.

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

Cited by 19 publications

References 19 publications

Estrogen receptor variant ER‐α36 promotes tamoxifen agonist activity in glioblastoma cells

Estrogen receptor variant ER‐α36 promotes tamoxifen agonist activity in glioblastoma cells

Knockdown of ER‐α36 expression inhibits glioma proliferation, invasion and epithelial‐to‐mesenchymal transition

Estrogen receptor variant ER‐α36 facilitates estrogen signaling via EGFR in glioblastoma

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