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
by
Heng-Wei Liu 1,2,3,4, Yu-Kai Su 1,2,3,4, Oluwaseun Adebayo Bamodu 4,5
, Dueng-Yuan Hueng 6, Wei-Hwa Lee 7, Chun-Chih Huang 8, Li Deng 9,10, Michael Hsiao 11, Ming-Hsien Chien 1, Chi-Tai Yeh 1,4,5,* and Chien-Min Lin 1,2,3,4,*
Heng-Wei Liu 1,2,3,4, Yu-Kai Su 1,2,3,4, Oluwaseun Adebayo Bamodu 4,5, Dueng-Yuan Hueng 6, Wei-Hwa Lee 7, Chun-Chih Huang 8, Li Deng 9,10, Michael Hsiao 11, Ming-Hsien Chien 1, Chi-Tai Yeh 1,4,5,* and Chien-Min Lin 1,2,3,4,*
1
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City 11031, Taiwan
2
Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 11031, Taiwan
3
Division of Neurosurgery, Department of Surgery, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
4
Taipei Neuroscience Institute, Taipei Medical University, Taipei 11031, Taiwan
5
Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
6
Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan, ROC
7
Department of Pathology, Taipei Medical University-Shuang Ho Hospital, Taipei 23561, Taiwan
8
Department of Applied Chemistry, Chaoyang University of Technology, Taichung 41147, Taiwan
9
Beijing Bioprocess Key Laboratory, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
10
Amoy-BUCT Industrial Bio-technovation Institute, Amoy 361022, China
11
Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan
*
Authors to whom correspondence should be addressed.
Cancers 2018, 10(12), 491; https://doi.org/10.3390/cancers10120491
Received: 3 November 2018 / Revised: 29 November 2018 / Accepted: 4 December 2018 / Published: 5 December 2018
(This article belongs to the Special Issue Glioblastoma: State of the Art and Future Perspectives)
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.
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Keywords:
glioblastoma; β-catenin; cancer stem cell; 4-AAQB; chemoresistance; prognosis; survival
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Description: Suppl. Figure S1. Aberrant expression of beta-catenin is characteristic of GBM and correlates with poor prognosis.
MDPI and ACS Style
Liu, H.-W.; Su, Y.-K.; Bamodu, O.A.; Hueng, D.-Y.; Lee, W.-H.; Huang, C.-C.; Deng, L.; Hsiao, M.; Chien, M.-H.; Yeh, C.-T.; Lin, C.-M. 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. Cancers 2018, 10, 491.
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