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

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.

• Authors: Yue Zhou, Chao Liang, Fei Xue, Wei Chen, Xiao Zhi, Xinhua Feng, Xueli Bai, Tingbo Liang
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 12 Pg. 10350-65 (Apr 30 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25871400 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• FOXO3 protein, human
• Forkhead Box Protein O3
• Forkhead Transcription Factors
• Pyrans
• TCF Transcription Factors
• beta Catenin
• salinomycin
• Doxorubicin

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Carcinoma, Hepatocellular (drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Doxorubicin (administration & dosage, pharmacology)
• Drug Resistance, Neoplasm
• Drug Synergism
• Forkhead Box Protein O3
• Forkhead Transcription Factors (genetics, metabolism)
• Humans
• Liver Neoplasms (drug therapy, genetics, metabolism)
• Male
• Mice
• Mice, Nude
• Pyrans (administration & dosage, pharmacology)
• Random Allocation
• TCF Transcription Factors (antagonists & inhibitors, metabolism)
• Transfection
• Xenograft Model Antitumor Assays
• beta Catenin (antagonists & inhibitors, metabolism)