Glioblastoma multiforme (GBM) is the most prevalent form of malignant brain tumor. Amlexanox, a novel compound, has been shown to have anti-cancer potential. In this study, the anti-tumoral effects and the underlying mechanisms of amlexanox were investigated. Amlexanox significantly suppressed proliferation and invasion and induced apoptosis in glioblastoma cells. Furthermore, we found that amlexanox altered the protein expression of the Hippo pathway by downregulating IKBKE. Our data indicates that IKBKE directly targets LATS1/2 and induces degradation of LATS1/2, thereby inhibiting the activity of the Hippo pathway. In vivo results further confirmed the tumor inhibitory effect of amlexanox via the downregulation of IKBKE, and amlexanox induced no apparent toxicity. Collectively, our studies suggest that amlexanox is a promising therapeutic agent for the treatment of GBM.
Resistance to antiestrogens is one of the major challenges in breast cancer treatment. Although phosphorylation of estrogen receptor α (ERα) is an important factor in endocrine resistance, the contributions of specific kinases in endocrine resistance are still not fully understood. Here, we report that an important innate immune response kinase, the IκB kinase-related TANK-binding kinase 1 (TBK1), is a crucial determinant of resistance to tamoxifen therapies. We show that TBK1 increases ERα transcriptional activity through phosphorylation modification of ERα at the Ser-305 site. Ectopic TBK1 expression impairs the responsiveness of breast cancer cells to tamoxifen. By studying the specimens from patients with breast cancer, we find a strong positive correlation of TBK1 with ERα, ERα Ser-305, and cyclin D1. Notably, patients with tumors highly expressing TBK1 respond poorly to tamoxifen treatment and show high potential for relapse. Therefore, our findings suggest that TBK1 contributes to tamoxifen resistance in breast cancer via phosphorylation modification of ERα.T ANK-binding kinase 1 (TBK1) and IκB kinase e (IKKe) are two IKK-related serine/threonine kinases that display 64% sequence identity and trigger the antiviral response of interferons (IFN) through NF-κB activation and interferon regulatory transcription factor (IRF) 3/7 phosphorylation (1-3). In addition to the proposed roles of IKK-related kinases in controlling transcription factors NF-κB and IRF, the involvement of TBK1 and IKKe in AKT-induced oncogenic transformation has been demonstrated in a recent study (4). TBK1 is identified as a Raslike (Ral) B effector in the Ral guanine nucleotide exchange factor pathway that is required for Ras-induced transformation (5). IKKe acts downstream of the PI3K-AKT pathway and cooperates with activated MEK to promote cellular transformation (6). IKKe has also been identified recently as a breast cancer oncogene that is frequently amplified or overexpressed in human breast cancer, and the phosphorylation of ERα by IKKe contributes to tamoxifen resistance in breast cancer (7-9). Interestingly, TBK1 is also highly expressed in breast cancer (10), and knocking down TBK1 diminishes the viability of MCF-7 cells (9). However, the exact role of TBK1 in breast cancer remains unclear.Estrogen receptor α (ERα) is a nuclear receptor that exerts a profound influence on the initiation and progression of breast cancer by regulating cell transformation, proliferation, and metastasis (11-13). For ERα-positive patients with breast cancer, targeting the ER signaling pathway with tamoxifen, a selective ER modulator, is efficacious in both prevention and treatment of breast cancer (14). Unfortunately, a substantial proportion of patients are intrinsically resistant to this therapy, and a significant number of patients with advanced disease eventually develop acquired resistance to the treatment (15-18). ERα is a key determinant of breast cancer susceptibility to endocrine therapy. Recent studies demonstrate that ERα phosphorylation ...
The transwell chamber migration assay and CCD digital camera imaging techniques were used to investigate the relationship between regulatory volume decrease (RVD) and cell migration in nasopharyngeal carcinoma cells (CNE-2Z cells). Both migrated and non-migrated CNE-2Z cells, when swollen by 47% hypotonic solution, exhibited RVD which was inhibited by extracellular application of chloride channel blockers adenosine 5'-triphosphate (ATP), 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and tamoxifen. However, RVD rate in migrated CNE-2Z cells was bigger than that of non-migrated cells and the sensitivity of migrated cells to NPPB and tamoxifen was higher than that of nonmigrated cells. ATP, NPPB and tamoxifen also inhibited migration of CNE-2Z cells. The inhibition of migration was positively correlated to the blockage of RVD, with a correlation coefficient (r) = 0.99, suggesting a functional relationship between RVD and cell migration. We conclude that RVD is involved in cell migration and RVD may play an important role in migratory process in CNE-2Z cells.
The use of single-crystal substrates as templates for the epitaxial growth of single-crystal overlayers has been a primary principle of materials epitaxy for more than 70 years. Here we report our finding that, though counterintuitive, single-crystal 2D materials can be epitaxially grown on twinned crystals. By establishing a geometric principle to describe 2D materials alignment on high-index surfaces, we show that 2D material islands grown on the two sides of a twin boundary can be well aligned. To validate this prediction, wafer-scale Cu foils with abundant twin boundaries were synthesized, and on the surfaces of these polycrystalline Cu foils, we have successfully grown wafer-scale single-crystal graphene and hexagonal boron nitride films. In addition, to greatly increasing the availability of large area high-quality 2D single crystals, our discovery also extends the fundamental understanding of materials epitaxy.
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