Journal
MOLECULAR CANCER THERAPEUTICS
Volume 15, Issue 12, Pages 2966-2976Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-16-0391
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Funding
- NUHS Basic seed grant [T1-BSRG 2015-02]
- John Nott Cancer Fellowship from Cancer Council, Western Australia
- Bench to Beside to Product grant [R-184-000-243-515]
- National Medical Research Council of Singapore [R-713-000-177-511]
- NCIS Yong Siew Yoon Research Grant
- National Research Foundation Singapore
- Singapore Ministry of Education under its Research Centres of Excellence initiative
- National Research Foundation of Korea grant - Korean government [NRF-2015R1A4A1042399]
- National Medical Research Council of Singapore
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Increasing evidence has indicated that epithelial-to-mesenchymal transition (EMT) at the advanced stage of liver cancer not only has the ability to self-renew and progress cancer, but also enables greater resistance to conventional chemo-and radiotherapies. Here, we report that ascochlorin (ASC), an isoprenoid antibiotic, could potentiate the cytotoxic effect of doxorubicin on HCCLM3, SNU387, SNU49, and SK-Hep-1 hepatocellular carcinoma cells, which had a predominantly mesenchymal signature with low expression of E-cadherin but high expression of N-cadherin. Co-administration of ASC reduced doxorubicin-induced invasion/migration and modulated EMT characteristics in mesenchymal cells. This process was probably mediated by the E-cadherin repressors Snail and Slug. In addition, ASC increased sensitivity to doxorubicin treatment by directly inhibiting STAT3 binding to the Snail promoter. We also observed that ASC significantly enhanced the effect of doxorubicin against tumor growth and inhibited metastasis in an HCCLM3_Luc orthotopic mouse model. Collectively, our data demonstrate that ASC can increase sensitivity to doxorubicin therapy and reverse the EMT phenotype via the downregulation of STAT3-Snail expression, which could form the basis of a novel therapeutic approach against hepatocellular carcinoma. (C) 2016 AACR.
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