Ascochlorin, an isoprenoid antibiotic inhibits growth and invasion of hepatocellular carcinoma by targeting STAT3 signaling cascade through the induction of PIAS3.

Abstract

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.

• Authors: Xiaoyun Dai, Kwang Seok Ahn, Chulwon Kim, Kodappully Sivaraman Siveen, Tina H Ong, Muthu K Shanmugam, Feng Li, Jizhong Shi, Alan Prem Kumar, Ling Zhi Wang, Boon Cher Goh, Junji Magae, Kam M Hui, Gautam Sethi
• Journal: Molecular oncology (Mol Oncol) Vol. 9 Issue 4 Pg. 818-33 (Apr 2015) ISSN: 1878-0261 [Electronic] United States
• PMID: 25624051 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Chemical References

• Alkenes
• Anti-Bacterial Agents
• Antineoplastic Agents
• Interleukin-6
• Ki-67 Antigen
• Molecular Chaperones
• PIAS3 protein, human
• Phenols
• Platelet Endothelial Cell Adhesion Molecule-1
• Protein Inhibitors of Activated STAT
• RNA, Messenger
• STAT3 Transcription Factor
• Epidermal Growth Factor
• DNA
• Caspases
• ascochlorin

Topics

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