ascochlorin and Liver-Neoplasms

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. Mol Cancer Ther; 15(12); 2966-76. ©2016 AACR.

Topics: Alkenes; Animals; Antibiotics, Antineoplastic; Apoptosis; Biomarkers; Carcinoma, Hepatocellular; Cell Line, Tumor; Disease Models, Animal; Doxorubicin; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Female; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Mice; Phenols; Snail Family Transcription Factors; STAT3 Transcription Factor

Deregulated activation of oncogenic transcription factors such as signal transducer and activator of transcription 3 (STAT3) plays a pivotal role in proliferation and survival of hepatocellular carcinoma (HCC). Thus, agents which can inhibit STAT3 activation may have an enormous potential for treatment of HCC patients. Hence, in the present report, we investigated the effect of ascochlorin (ASC), an isoprenoid antibiotic on STAT3 activation cascade in various HCC cell lines and orthotopic mouse model. We observed that ASC could substantially inhibit both constitutive and IL-6/EGF inducible STAT3 activation as well as reduce its DNA binding ability. ASC increased the expression of protein inhibitor of activated STAT3 (PIAS3) which could bind to STAT3 DNA binding domain and thereby down-regulate STAT3 activation. Deletion of PIAS3 gene by siRNA abolished the ability of ASC to inhibit STAT3 activation and induce apoptosis in HCC cells. ASC also modulated the expression of diverse STAT3-regulated oncogenic gene products. Finally, when administered intraperitoneally, ASC also inhibited tumor growth in an orthotopic HCC mouse model and reduced STAT3 activation in tumor tissues. Overall our results indicate that ASC mediates its anti-tumor effects predominantly through the suppression of STAT3 signaling cascade, and can form the basis of novel therapy for HCC patients.

Topics: Alkenes; Animals; Anti-Bacterial Agents; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Caspases; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Proliferation; Cell Survival; DNA; Epidermal Growth Factor; Gene Expression Regulation, Neoplastic; Humans; Interleukin-6; Ki-67 Antigen; Liver Neoplasms; Mice; Molecular Chaperones; Neoplasm Invasiveness; Phenols; Phosphorylation; Platelet Endothelial Cell Adhesion Molecule-1; Protein Binding; Protein Inhibitors of Activated STAT; Protein Transport; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor