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Salinomycin decreases doxorubicin resistance in hepatocellular carcinoma cells by inhibiting the β-catenin/TCF complex association via FOXO3a activation.

Zhou Y, Liang C, Xue F, Chen W, Zhi X, Feng X, Bai X, Liang T - Oncotarget (2015)

Bottom Line: However, during long-term doxorubicin monotherapy, HCC cells may eventually develop acquired-resistance to doxorubicin which results in recurrence and a poor prognosis.In addition, activated FOXO3a disturbed the interaction between β-catenin and TCF and inhibited the expression of β-catenin/TCF target genes (ZEB1, c-Myc and CyclinD1), which played important roles in doxorubicin-induced EMT in HCC cells.Finally, the enhanced curative efficacy of combination treatment of doxorubicin and salinomycin for HCC was confirmed in established xenograft models.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, PR China.

ABSTRACT
Doxorubicin is a conventional and effective chemotherapy drug against hepatocellular carcinoma (HCC). However, during long-term doxorubicin monotherapy, HCC cells may eventually develop acquired-resistance to doxorubicin which results in recurrence and a poor prognosis. Salinomycin, an ionophore antibiotic, was recently reported to selectively kill human cancer stem cells (CSCs) which were response for chemoresistance. In this study, salinomycin was found to exert synergistic cytotoxicity with doxorubicin in HCC cells and be capable of inhibiting doxorubicin-induced epithelial-mesenchymal transition (EMT), an important cellular process involved in the acquired chemoresistance of tumors. Further experiments revealed that FOXO3a, a multifunctional transcription factor that can be activated by salinomycin, was vital in mediating doxorubicin-induced EMT. In addition, activated FOXO3a disturbed the interaction between β-catenin and TCF and inhibited the expression of β-catenin/TCF target genes (ZEB1, c-Myc and CyclinD1), which played important roles in doxorubicin-induced EMT in HCC cells. Finally, the enhanced curative efficacy of combination treatment of doxorubicin and salinomycin for HCC was confirmed in established xenograft models. In summary, the present study identifies a new doxorubicin-based chemotherapy for advanced HCC and provides a potential anti-cancer strategy targeting FOXO3a and related cell pathway molecules.

No MeSH data available.


Related in: MedlinePlus

Salinomycin alters the expression of doxorubicin-induced EMT-markers in HCC cells(A) Expression of the EMT markers E-cadherin and Vimentin examined by western blotting in control HCC cells, HCC cells treated with doxorubicin (0.25μg/ml), doxorubicin (0.25μg/ml) plus salinomycin (10μM) or salinomycin (10μM) alone for 48 h. (B) Normalized ratios of E-cadherin/Vimentin calculated by analyzing the densities of western bolt bands (* p < 0.05, ** p < 0.01 for control vs. doxorubicin alone; # p < 0.05, ## p < 0.01 for doxorubicin plus salinomycin vs. doxorubicin alone; & p < 0.05, && p < 0.01 for control vs. salinomycin alone). (C) Distribution of E-cadherin detected by immunofluorescence in (a) HuH-7, (b) HepG2, (c) SNU-449 and (d) SNU-387 cells treated for 48 h with doxorubicin (0.25μg/ml) in the presence or absence of salinomycin (10μM).
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Figure 2: Salinomycin alters the expression of doxorubicin-induced EMT-markers in HCC cells(A) Expression of the EMT markers E-cadherin and Vimentin examined by western blotting in control HCC cells, HCC cells treated with doxorubicin (0.25μg/ml), doxorubicin (0.25μg/ml) plus salinomycin (10μM) or salinomycin (10μM) alone for 48 h. (B) Normalized ratios of E-cadherin/Vimentin calculated by analyzing the densities of western bolt bands (* p < 0.05, ** p < 0.01 for control vs. doxorubicin alone; # p < 0.05, ## p < 0.01 for doxorubicin plus salinomycin vs. doxorubicin alone; & p < 0.05, && p < 0.01 for control vs. salinomycin alone). (C) Distribution of E-cadherin detected by immunofluorescence in (a) HuH-7, (b) HepG2, (c) SNU-449 and (d) SNU-387 cells treated for 48 h with doxorubicin (0.25μg/ml) in the presence or absence of salinomycin (10μM).

Mentions: Furthermore, doxorubicin significantly reduced the expression of E-cadherin and upregulated Vimentin in HCC cells compared to the untreated control, whereas salinomycin reversed doxorubicin-induced expression changes of EMT-markers (Fig. 2A and B). In addition, the expression of E-cadherin was detected by immunofluorescence, to further confirm the above-mentioned EMT in HCC cells regulated by doxorubicin and salinomycin (Fig. 2C). The results of immunofluorescent staining were consistent with the western blotting.


Salinomycin decreases doxorubicin resistance in hepatocellular carcinoma cells by inhibiting the β-catenin/TCF complex association via FOXO3a activation.

Zhou Y, Liang C, Xue F, Chen W, Zhi X, Feng X, Bai X, Liang T - Oncotarget (2015)

Salinomycin alters the expression of doxorubicin-induced EMT-markers in HCC cells(A) Expression of the EMT markers E-cadherin and Vimentin examined by western blotting in control HCC cells, HCC cells treated with doxorubicin (0.25μg/ml), doxorubicin (0.25μg/ml) plus salinomycin (10μM) or salinomycin (10μM) alone for 48 h. (B) Normalized ratios of E-cadherin/Vimentin calculated by analyzing the densities of western bolt bands (* p < 0.05, ** p < 0.01 for control vs. doxorubicin alone; # p < 0.05, ## p < 0.01 for doxorubicin plus salinomycin vs. doxorubicin alone; & p < 0.05, && p < 0.01 for control vs. salinomycin alone). (C) Distribution of E-cadherin detected by immunofluorescence in (a) HuH-7, (b) HepG2, (c) SNU-449 and (d) SNU-387 cells treated for 48 h with doxorubicin (0.25μg/ml) in the presence or absence of salinomycin (10μM).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4496360&req=5

Figure 2: Salinomycin alters the expression of doxorubicin-induced EMT-markers in HCC cells(A) Expression of the EMT markers E-cadherin and Vimentin examined by western blotting in control HCC cells, HCC cells treated with doxorubicin (0.25μg/ml), doxorubicin (0.25μg/ml) plus salinomycin (10μM) or salinomycin (10μM) alone for 48 h. (B) Normalized ratios of E-cadherin/Vimentin calculated by analyzing the densities of western bolt bands (* p < 0.05, ** p < 0.01 for control vs. doxorubicin alone; # p < 0.05, ## p < 0.01 for doxorubicin plus salinomycin vs. doxorubicin alone; & p < 0.05, && p < 0.01 for control vs. salinomycin alone). (C) Distribution of E-cadherin detected by immunofluorescence in (a) HuH-7, (b) HepG2, (c) SNU-449 and (d) SNU-387 cells treated for 48 h with doxorubicin (0.25μg/ml) in the presence or absence of salinomycin (10μM).
Mentions: Furthermore, doxorubicin significantly reduced the expression of E-cadherin and upregulated Vimentin in HCC cells compared to the untreated control, whereas salinomycin reversed doxorubicin-induced expression changes of EMT-markers (Fig. 2A and B). In addition, the expression of E-cadherin was detected by immunofluorescence, to further confirm the above-mentioned EMT in HCC cells regulated by doxorubicin and salinomycin (Fig. 2C). The results of immunofluorescent staining were consistent with the western blotting.

Bottom Line: However, during long-term doxorubicin monotherapy, HCC cells may eventually develop acquired-resistance to doxorubicin which results in recurrence and a poor prognosis.In addition, activated FOXO3a disturbed the interaction between β-catenin and TCF and inhibited the expression of β-catenin/TCF target genes (ZEB1, c-Myc and CyclinD1), which played important roles in doxorubicin-induced EMT in HCC cells.Finally, the enhanced curative efficacy of combination treatment of doxorubicin and salinomycin for HCC was confirmed in established xenograft models.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, PR China.

ABSTRACT
Doxorubicin is a conventional and effective chemotherapy drug against hepatocellular carcinoma (HCC). However, during long-term doxorubicin monotherapy, HCC cells may eventually develop acquired-resistance to doxorubicin which results in recurrence and a poor prognosis. Salinomycin, an ionophore antibiotic, was recently reported to selectively kill human cancer stem cells (CSCs) which were response for chemoresistance. In this study, salinomycin was found to exert synergistic cytotoxicity with doxorubicin in HCC cells and be capable of inhibiting doxorubicin-induced epithelial-mesenchymal transition (EMT), an important cellular process involved in the acquired chemoresistance of tumors. Further experiments revealed that FOXO3a, a multifunctional transcription factor that can be activated by salinomycin, was vital in mediating doxorubicin-induced EMT. In addition, activated FOXO3a disturbed the interaction between β-catenin and TCF and inhibited the expression of β-catenin/TCF target genes (ZEB1, c-Myc and CyclinD1), which played important roles in doxorubicin-induced EMT in HCC cells. Finally, the enhanced curative efficacy of combination treatment of doxorubicin and salinomycin for HCC was confirmed in established xenograft models. In summary, the present study identifies a new doxorubicin-based chemotherapy for advanced HCC and provides a potential anti-cancer strategy targeting FOXO3a and related cell pathway molecules.

No MeSH data available.


Related in: MedlinePlus