title: 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.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Dai
authors.affiliation: College of Oriental Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
authors.affiliation: College of Oriental Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Chulwon
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
authors.forename: Kodappully Sivaraman
authors.initials: KS
authors.lastname: Siveen
authors.affiliation: Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore.
authors.forename: Tina H
authors.initials: TH
authors.lastname: Ong
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
authors.forename: Muthu K
authors.initials: MK
authors.lastname: Shanmugam
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore; Cancer Science Institute of Singapore, Centre for Translational Medicine, 14 Medical Drive, #11-01M, Singapore 117599, Singapore.
authors.forename: Jizhong
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore; Cancer Science Institute of Singapore, Centre for Translational Medicine, 14 Medical Drive, #11-01M, Singapore 117599, Singapore; School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Western Australia 6009, Australia; Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA.
authors.forename: Alan Prem
authors.initials: AP
authors.lastname: Kumar
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore; Cancer Science Institute of Singapore, Centre for Translational Medicine, 14 Medical Drive, #11-01M, Singapore 117599, Singapore.
authors.forename: Ling Zhi
authors.initials: LZ
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore; Cancer Science Institute of Singapore, Centre for Translational Medicine, 14 Medical Drive, #11-01M, Singapore 117599, Singapore; Department of Haematology-Oncology, National University Health System, Singapore 117597, Singapore.
authors.forename: Boon Cher
authors.initials: BC
authors.lastname: Goh
authors.affiliation: Magae Bioscience Institute, 49-4 Fujimidai, Tsukuba 300-1263, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Magae
authors.affiliation: Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore; Institute of Molecular and Cell Biology, A*STAR, Biopolis Drive Proteos, Singapore; Cancer and Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: cmrhkm@nccs.com.sg.
authors.forename: Kam M
authors.initials: KM
authors.lastname: Hui
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore; School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Western Australia 6009, Australia. Electronic address: phcgs@nus.edu.sg.
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
mesh_terms: D000475:Alkenes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000475:Alkenes; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D015850:Interleukin-6; D019394:Ki-67 Antigen; D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D010636:Phenols; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D050828:Protein Inhibitors of Activated STAT; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D004815:Epidermal Growth Factor; D004247:DNA; D020169:Caspases; C415745:ascochlorin
keywords: Ascochlorin; HCC; Invasion; Orthotopic model; PIAS3; STAT3