Oncotarget

Research Papers:

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

Yue Zhou, Chao Liang, Fei Xue, Wei Chen, Xiao Zhi, Xinhua Feng, Xueli Bai and Tingbo Liang _

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Oncotarget. 2015; 6:10350-10365. https://doi.org/10.18632/oncotarget.3585

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Abstract

Yue Zhou1,*, Chao Liang1,*, Fei Xue2,*, Wei Chen1, Xiao Zhi1, Xinhua Feng3, Xueli Bai1 and Tingbo Liang1

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

2 Department of Hepatobiliary and Pancreatic Surgery, People’s Hospital of Zhengzhou University, School of Medicine, Zhengzhou University, Zhengzhou, PR China

3 Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, PR China

* These authors contributed equally to this work

Correspondence to:

Tingbo Liang, email:

Xueli Bai, email:

Keywords: hepatocellular carcinoma, salinomycin, doxorubicin, EMT, FOXO3a

Received: December 21, 2014 Accepted: February 13, 2015 Published: March 14, 2015

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.


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