The Disruption of the β-Catenin/TCF-1/STAT3 Signaling Axis by 4-Acetylantroquinonol B Inhibits the Tumorigenesis and Cancer Stem-Cell-Like Properties of Glioblastoma Cells, In Vitro and In Vivo

Abstract

Background: Glioblastoma (GBM), a malignant form of glioma, is characterized by resistance to therapy and poor prognosis. Accumulating evidence shows that the initiation, propagation, and recurrence of GBM is attributable to the presence of GBM stem cells (GBM-CSCs). Experimental approach: Herein, we investigated the effect of 4-Acetylantroquinonol B (4-AAQB), a bioactive isolate of Antrodia cinnamomea, on GBM cell viability, oncogenic, and CSCs-like activities. Results: We observed that aberrant expression of catenin is characteristic of GBM, compared to other glioma types (p = 0.0001, log-rank test = 475.2), and correlates with poor prognosis of GBM patients. Lower grade glioma and glioblastoma patients (n = 1152) with low catenin expression had 25% and 21.5% better overall survival than those with high catenin expression at the 5 and 10-year time-points, respectively (p = 3.57e-11, log-rank test = 43.8). Immunohistochemistry demonstrated that compared with adjacent non-tumor brain tissue, primary and recurrent GBM exhibited enhanced catenin expression (~10-fold, p < 0.001). Western blot analysis showed that 4-AAQB significantly downregulated β-catenin and dysregulated the catenin/LEF1/Stat3 signaling axis in U87MG and DBTRG-05MG cells, dose-dependently. 4-AAQB–induced downregulation of catenin positively correlated with reduced Sox2 and Oct4 nuclear expression in the cells. Furthermore, 4-AAQB markedly reduced the viability of U87MG and DBTRG-05MG cells with 48 h IC50 of 9.2 M and 12.5 M, respectively, effectively inhibited the nuclear catenin, limited the migration and invasion of GBM cells, with concurrent downregulation of catenin, vimentin, and slug; similarly, colony and tumorsphere formation was significantly attenuated with reduced expression of c-Myc and KLF4 proteins. Conclusions: Summarily, we show for the first time that 4-AAQB suppresses the tumor-promoting catenin/LEF1/Stat3 signaling, and inhibited CSCs-induced oncogenic activities in GBM in vitro, with in vivo validation; thus projecting 4-AAQB as a potent therapeutic agent for anti-GBM target therapy.

Targeting IL-3Rα on tumor-derived endothelial cells blunts metastatic spread of triple-negative breast cancer via extracellular vesicle reprogramming

“…Quantifications of Vimentin-and TWIST1-positive area were performed using Fiji software 60 . The analysis of β-catenin-positive cells was performed by two independent pathologists and expressed as Quick score (Q) 61 . MDA-MB-231 cells were detected in livers and lungs by immunofluorescence using anti-HLA I (Santa Cruz Biotechnology, #sc-25619).…”

Satellite Cells and Markers of Muscle Regeneration during Unloading and Reloading: Effects of Treatment with Resveratrol and Curcumin

“…Administration of resveratrol or curcumin using other routes (oral, during food or water administration) would not allow us to ensure an identical dose for each mouse. Furthermore, intraperitoneal administration avoids absorption through the gastrointestinal tract and the first barrier of the hepatic metabolism, as generally happens in oral administration [ 39 , 40 ]. Accordingly, intraperitoneal injection was the selected route due to the fact that it gets into the circulation faster than other routes (oral gavage), to ensure the optimal absorption of the two compounds in view of its short bioavailability in plasma, estimated as 15–60 min in mice [ 36 , 37 , 38 ].…”

The long non-coding RNA, urothelial carcinoma associated 1, promotes cell growth, invasion, migration, and chemo-resistance in glioma through Wnt/β-catenin signaling pathway

“…Wnt/β-catenin signaling pathway plays essential roles in human malignancies including glioma [19]. Disruption of Wnt/β-catenin signaling has been shown to inhibit the tumorigenesis of glioma [20]. Recently, studies found that UCA1 was effective to enhance the activities of Wnt/β-catenin in several types of cancers including melanoma [21], breast cancer [17], osteosarcoma [22] and oral squamous cell carcinoma [23].…”