The location of estrogen receptor variant ER-?36 is associated with the invasion of glioblastoma

Glioblastoma (GBM) is the most common central nervous system tumor and is associated with poor outcomes. There have been no significant improvements in GBM mortality in recent decades. ER-alpha 36 is a variant of ER-alpha 66 that may be involved in carcinoma growth and proliferation via genomic and nongenomic mechanisms. This variant might play an essential role in tamoxifen resistance of several tumors. Previously, our laboratory found that ER-alpha 36 is expressed in GBM and participates in proliferation; nevertheless, the role of ER-alpha 36 in GBM in-vasion remains unknown. This study aimed to determine the effects of the ER-alpha 36 modulator SNG162 on GBM growth and invasion. U251 cells, U87cells, and U87-36KD cells with knockdown of ER-alpha 36 expression were cultured under the two-dimensional and the three-dimensional (3D) environments. GBM cells growth was examined by cell counting, flow cytometry, western blot, and MTT assays. Invasiveness was measured using confocal microscopy in the 3D environment. Growth of U87 cells with downregulated EGFR and ER-alpha 36 expression was significantly reduced after treatment with 1 mu M, 3 mu M, and 5 mu M of SNG162; growth inhibition in U251 cells was more potent than in U87 cells, although the expression level of ER-alpha 36 in U251 cells was lower than in U87 cells. We found that 1 mu M SNG162 suppressed E2-induced MAPK/ERK pathway activation in U87 cells. We also showed that SNG162 inhibited U87 cells invasion; however, it did not significantly affect U251 and U87-36KD cells invasion using the 3D culture method. Finally, we determined that ER-alpha 36 was expressed in the nucleus of invading GBM cells, and SNG162 significantly inhibited the expression of ER-alpha 36 in these cells. SNG162 inhibited the expression of EGFR on cell membranes of non-invasive GBM cells. These results suggest that SNG162 could be a therapeutic agent for GBM by targeting ER-alpha 36.