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

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

  • Mol Oncol. 2015 Apr;9(4):818-33. doi: 10.1016/j.molonc.2014.12.008.
Xiaoyun Dai 1,  Kwang Seok Ahn 2,  Chulwon Kim 2,  Kodappully Sivaraman Siveen 1,  Tina H Ong 3,  Muthu K Shanmugam 1,  Feng Li 1,  Jizhong Shi 4,  Alan Prem Kumar 5,  Ling Zhi Wang 4,  Boon Cher Goh 6,  Junji Magae 7,  Kam M Hui 8,  Gautam Sethi 9
Affiliations

Affiliations

  • 1 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
  • 2 College of Oriental Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
  • 3 Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore.
  • 4 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.
  • 5 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.
  • 6 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.
  • 7 Magae Bioscience Institute, 49-4 Fujimidai, Tsukuba 300-1263, Japan.
  • 8 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.
  • 9 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.
PMID: 25624051 DOI: 10.1016/j.molonc.2014.12.008
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.

Keywords

Ascochlorin; HCC; Invasion; Orthotopic model; PIAS3; STAT3.

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