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

Heng Wei Liu, Yu-Kai Su, Oluwaseun Adebayo Bamodu, Dueng Yuan Hueng, Wei Hwa Lee, Chun Chih Huang, Li Deng, Michael Hsiao, Ming Hsien Chien, Chi Tai Yeh, Chien Min Lin

研究成果: 雜誌貢獻文章

4 引文 (Scopus)

摘要

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.
原文英語
文章編號491
期刊Cancers
10
發行號12
DOIs
出版狀態已發佈 - 十二月 1 2018

指紋

Catenins
Neoplastic Stem Cells
Glioblastoma
Carcinogenesis
Glioma
Down-Regulation
In Vitro Techniques
Antrodia
Proto-Oncogene Proteins c-myc
Gastropoda
Vimentin
Inhibitory Concentration 50
Cell Survival
Stem Cells
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

引用此文

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. / Liu, Heng Wei; Su, Yu-Kai; Bamodu, Oluwaseun Adebayo; Hueng, Dueng Yuan; Lee, Wei Hwa; Huang, Chun Chih; Deng, Li; Hsiao, Michael; Chien, Ming Hsien; Yeh, Chi Tai; Lin, Chien Min.

於: Cancers, 卷 10, 編號 12, 491, 01.12.2018.

研究成果: 雜誌貢獻文章

Liu, Heng Wei ; Su, Yu-Kai ; Bamodu, Oluwaseun Adebayo ; Hueng, Dueng Yuan ; Lee, Wei Hwa ; Huang, Chun Chih ; Deng, Li ; Hsiao, Michael ; Chien, Ming Hsien ; Yeh, Chi Tai ; Lin, Chien Min. / 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. 於: Cancers. 2018 ; 卷 10, 編號 12.
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title = "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.",
keywords = "4-AAQB, Cancer stem cell, Chemoresistance, Glioblastoma, Prognosis, Survival, β-catenin",
author = "Liu, {Heng Wei} and Yu-Kai Su and Bamodu, {Oluwaseun Adebayo} and Hueng, {Dueng Yuan} and Lee, {Wei Hwa} and Huang, {Chun Chih} and Li Deng and Michael Hsiao and Chien, {Ming Hsien} and Yeh, {Chi Tai} and Lin, {Chien Min}",
year = "2018",
month = "12",
day = "1",
doi = "10.3390/cancers10120491",
language = "English",
volume = "10",
journal = "Cancers",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "12",

}

TY - JOUR

T1 - 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

AU - Liu, Heng Wei

AU - Su, Yu-Kai

AU - Bamodu, Oluwaseun Adebayo

AU - Hueng, Dueng Yuan

AU - Lee, Wei Hwa

AU - Huang, Chun Chih

AU - Deng, Li

AU - Hsiao, Michael

AU - Chien, Ming Hsien

AU - Yeh, Chi Tai

AU - Lin, Chien Min

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

KW - 4-AAQB

KW - Cancer stem cell

KW - Chemoresistance

KW - Glioblastoma

KW - Prognosis

KW - Survival

KW - β-catenin

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U2 - 10.3390/cancers10120491

DO - 10.3390/cancers10120491

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VL - 10

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JF - Cancers

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