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.
Highlights
Glioblastoma (GBM), one of the most lethal malignancies in adults, with an average incidence of 3.2/100 000, median survival of about 15 months, and median age at diagnosis of 64 years, is the most common and highly aggressive brain tumor [1]
Our analyses revealed the histological subtypes of glioma with the poorest overall survival were characterized by the most aberrantly expressed β-catenin gene expression as demonstrated by a median β-catenin expression of 13.125 in patients with GBM, treated primary GBM and untreated primary GBM, compared to 12.80, 12.69, and 12.70 in those with astrocytoma, oligoastrocytoma and oligodendroglioma, respectively (Figure 1B)
U133 Plus 2.0 Array dataset, we examined the expression profile of β-catenin (1554411_at) in cultures (HG-U133_Plus_2) Affymetrix Human Genome U133 Plus 2.0 Array dataset, we examined the of progenitor (GBM-SCs) and four-day differentiated GBM cells derived from surgical specimens; our expression profile of β-catenin (1554411_at) in cultures of progenitor (GBM-SCs) and four-day data show that compared to the differentiated GBM cells in samples GSM520521, GSM520523, and differentiated GBM cells derived from surgical specimens; our data show that compared to the
Summary
Glioblastoma (GBM), one of the most lethal malignancies in adults, with an average incidence of 3.2/100 000, median survival of about 15 months, and median age at diagnosis of 64 years, is the most common and highly aggressive brain tumor [1]. Current anti-GBM therapeutic strategy consisting of concurrent chemoradiotherapy (CCRT) with the DNA alkylating agent, temozolomide (TMZ), is plagued by eventual disease relapse and only prolongs the median survival to 14.6 months [3], necessitating the discovery and/or development of new therapeutic strategy with high anti-GBM efficacy. In their published review, Vogelstein et al [4] analyzed several alterations in the human cancer genome and identified tumor driver or promoter genes, as well as outlined twelve associated signaling pathways including Notch, Hedgehog (Hh), and Wnt/β-catenin, known to regulate the determination of cell fate, survival, proliferation, and genome stability. Experimental approach: 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
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