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FOXM1 confers to epithelial-mesenchymal transition, stemness and chemoresistance in epithelial ovarian carcinoma cells.

Chiu WT, Huang YF, Tsai HY, Chen CC, Chang CH, Huang SC, Hsu KF, Chou CY - Oncotarget (2015)

Bottom Line: Chemoresistance to anti-cancer drugs substantially reduces survival in epithelial ovarian cancer.Conversely, depletion of FOXM1 via RNA interference reduced cisplatin resistance and sphere formation in cisplatin-resistant and high FOXM1-expressing cells.The combination of cisplatin and the FOXM1 inhibitor thiostrepton inhibited the expression of stem cell markers in chemoresistant cells and subcutaneous ovarian tumor growth in mouse xenografts.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan.

ABSTRACT
Chemoresistance to anti-cancer drugs substantially reduces survival in epithelial ovarian cancer. In this study, we showed that chemoresistance to cisplatin and paclitaxel induced the epithelial-mesenchymal transition (EMT) and a stem cell phenotype in ovarian cancer cells. Chemoresistance was associated with the downregulation of epithelial markers and the upregulation of mesenchymal markers, EMT-related transcription factors, and cancer stem cell markers, which enhanced invasion and sphere formation ability. Overexpression of FOXM1 increased cisplatin-resistance and sphere formation in cisplatin-sensitive and low FOXM1-expressing ovarian cancer cells. Conversely, depletion of FOXM1 via RNA interference reduced cisplatin resistance and sphere formation in cisplatin-resistant and high FOXM1-expressing cells. Overexpression of FOXM1 also increased the expression, nuclear accumulation, and activity of β-CATENIN in chemoresistant cells, whereas downregulation of FOXM1 suppressed these events. The combination of cisplatin and the FOXM1 inhibitor thiostrepton inhibited the expression of stem cell markers in chemoresistant cells and subcutaneous ovarian tumor growth in mouse xenografts. In an analysis of 106 ovarian cancer patients, high FOXM1 levels in tumors were associated with cancer progression and short progression-free intervals. Collectively, our findings highlight the importance of FOXM1 in chemoresistance and suggest that FOXM1 inhibitors may be useful for treatment of ovarian cancer.

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Thiostrepton inhibits the growth of cisplatin-resistant ovarian cancer cells in vitro and in vivo(A) A2780CP70 (CP70) cells were treated with 0, 0.5, 1, or 2 μM thiostrepton (Thio) and various concentration of cisplatin (Cis) for 48 hours. Cisplatin resistance was determined via MTT assay. The insets show the western blots for FOXM1 and the internal control β-ACTIN. (B and C). CP70 cells were injected subcutaneously into the right scapular region of NOD/SCID mice; mice then received Cis and/or Thio as described in Materials and Methods. Tumor growth curves (B) and photographs of isolated tumors (C) are shown. *: significant difference between treated and control (Ctrl) cells (A) or B (mice). *: P < 0.05; ***: P < 0.001. (B) #: significant difference between single and combined (Cis + Thio) treatments. #: P < 0.05; ##: P < 0.01.
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Figure 10: Thiostrepton inhibits the growth of cisplatin-resistant ovarian cancer cells in vitro and in vivo(A) A2780CP70 (CP70) cells were treated with 0, 0.5, 1, or 2 μM thiostrepton (Thio) and various concentration of cisplatin (Cis) for 48 hours. Cisplatin resistance was determined via MTT assay. The insets show the western blots for FOXM1 and the internal control β-ACTIN. (B and C). CP70 cells were injected subcutaneously into the right scapular region of NOD/SCID mice; mice then received Cis and/or Thio as described in Materials and Methods. Tumor growth curves (B) and photographs of isolated tumors (C) are shown. *: significant difference between treated and control (Ctrl) cells (A) or B (mice). *: P < 0.05; ***: P < 0.001. (B) #: significant difference between single and combined (Cis + Thio) treatments. #: P < 0.05; ##: P < 0.01.

Mentions: Our findings suggest that FOXM1 promotes the formation of CSCs and chemoresistance. We asked whether inhibiting FOXM1 activity could be an effective therapeutic strategy in chemoresistant ovarian cancer. As shown in Figs. 10A and S2, the FOXM1 inhibitor thiostrepton decreased the expression of FOXM1 and stem cell markers in a dose-dependent manner in A2780CP70 cells. Pretreatment of cells with thiostrepton sensitized cisplatin-resistant A2780CP70 cells to cisplatin (Fig. 10A; P < 0.001, one-way ANOVA). Thiostrepton and cisplatin inhibited the growth of A2780CP70 cells in mouse xenografts compared with the vehicle control, and the combination of cisplatin and thiostrepton was more effective than either alone (Fig. 10B, C; P = 0.004, Kruskal-Wallis test).


FOXM1 confers to epithelial-mesenchymal transition, stemness and chemoresistance in epithelial ovarian carcinoma cells.

Chiu WT, Huang YF, Tsai HY, Chen CC, Chang CH, Huang SC, Hsu KF, Chou CY - Oncotarget (2015)

Thiostrepton inhibits the growth of cisplatin-resistant ovarian cancer cells in vitro and in vivo(A) A2780CP70 (CP70) cells were treated with 0, 0.5, 1, or 2 μM thiostrepton (Thio) and various concentration of cisplatin (Cis) for 48 hours. Cisplatin resistance was determined via MTT assay. The insets show the western blots for FOXM1 and the internal control β-ACTIN. (B and C). CP70 cells were injected subcutaneously into the right scapular region of NOD/SCID mice; mice then received Cis and/or Thio as described in Materials and Methods. Tumor growth curves (B) and photographs of isolated tumors (C) are shown. *: significant difference between treated and control (Ctrl) cells (A) or B (mice). *: P < 0.05; ***: P < 0.001. (B) #: significant difference between single and combined (Cis + Thio) treatments. #: P < 0.05; ##: P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385856&req=5

Figure 10: Thiostrepton inhibits the growth of cisplatin-resistant ovarian cancer cells in vitro and in vivo(A) A2780CP70 (CP70) cells were treated with 0, 0.5, 1, or 2 μM thiostrepton (Thio) and various concentration of cisplatin (Cis) for 48 hours. Cisplatin resistance was determined via MTT assay. The insets show the western blots for FOXM1 and the internal control β-ACTIN. (B and C). CP70 cells were injected subcutaneously into the right scapular region of NOD/SCID mice; mice then received Cis and/or Thio as described in Materials and Methods. Tumor growth curves (B) and photographs of isolated tumors (C) are shown. *: significant difference between treated and control (Ctrl) cells (A) or B (mice). *: P < 0.05; ***: P < 0.001. (B) #: significant difference between single and combined (Cis + Thio) treatments. #: P < 0.05; ##: P < 0.01.
Mentions: Our findings suggest that FOXM1 promotes the formation of CSCs and chemoresistance. We asked whether inhibiting FOXM1 activity could be an effective therapeutic strategy in chemoresistant ovarian cancer. As shown in Figs. 10A and S2, the FOXM1 inhibitor thiostrepton decreased the expression of FOXM1 and stem cell markers in a dose-dependent manner in A2780CP70 cells. Pretreatment of cells with thiostrepton sensitized cisplatin-resistant A2780CP70 cells to cisplatin (Fig. 10A; P < 0.001, one-way ANOVA). Thiostrepton and cisplatin inhibited the growth of A2780CP70 cells in mouse xenografts compared with the vehicle control, and the combination of cisplatin and thiostrepton was more effective than either alone (Fig. 10B, C; P = 0.004, Kruskal-Wallis test).

Bottom Line: Chemoresistance to anti-cancer drugs substantially reduces survival in epithelial ovarian cancer.Conversely, depletion of FOXM1 via RNA interference reduced cisplatin resistance and sphere formation in cisplatin-resistant and high FOXM1-expressing cells.The combination of cisplatin and the FOXM1 inhibitor thiostrepton inhibited the expression of stem cell markers in chemoresistant cells and subcutaneous ovarian tumor growth in mouse xenografts.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan.

ABSTRACT
Chemoresistance to anti-cancer drugs substantially reduces survival in epithelial ovarian cancer. In this study, we showed that chemoresistance to cisplatin and paclitaxel induced the epithelial-mesenchymal transition (EMT) and a stem cell phenotype in ovarian cancer cells. Chemoresistance was associated with the downregulation of epithelial markers and the upregulation of mesenchymal markers, EMT-related transcription factors, and cancer stem cell markers, which enhanced invasion and sphere formation ability. Overexpression of FOXM1 increased cisplatin-resistance and sphere formation in cisplatin-sensitive and low FOXM1-expressing ovarian cancer cells. Conversely, depletion of FOXM1 via RNA interference reduced cisplatin resistance and sphere formation in cisplatin-resistant and high FOXM1-expressing cells. Overexpression of FOXM1 also increased the expression, nuclear accumulation, and activity of β-CATENIN in chemoresistant cells, whereas downregulation of FOXM1 suppressed these events. The combination of cisplatin and the FOXM1 inhibitor thiostrepton inhibited the expression of stem cell markers in chemoresistant cells and subcutaneous ovarian tumor growth in mouse xenografts. In an analysis of 106 ovarian cancer patients, high FOXM1 levels in tumors were associated with cancer progression and short progression-free intervals. Collectively, our findings highlight the importance of FOXM1 in chemoresistance and suggest that FOXM1 inhibitors may be useful for treatment of ovarian cancer.

Show MeSH
Related in: MedlinePlus