Increasing evidence(s) have 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 radio-therapies. Here, we report that ascochlorin (ASC), an isoprenoid antibiotic could potentiate the cytotoxic effect of doxorubicin (DOX) on HCCLM3, SNU387, SNU49, and SK-Hep-1 hepatocellular carcinoma (HCC) cells, which had a predominantly mesenchymal signature with low expression of E-cadherin but high expression of N-cadherin. Co-administration of ASC reduced DOX-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 DOX treatment by directly inhibiting STAT3 binding to the Snail promoter. We also observed that ASC significantly enhanced the effect of DOX against tumor growth and inhibited metastasis in an HCCLM3_Luc orthotopic mouse model. Collectively, our data demonstrate that ASC can increase sensitivity to DOX therapy and reverse the EMT phenotype via the down-regulation of STAT3-Snail expression, which could form the basis of a novel therapeutic approach against HCC.
- Received June 16, 2016.
- Revision received August 31, 2016.
- Accepted September 19, 2016.
- Copyright ©2016, American Association for Cancer Research.