title: Emodin inhibits growth and induces apoptosis in an orthotopic hepatocellular carcinoma model by blocking activation of STAT3.
abstract: OBJECTIVE
  Aberrant activation of STAT3 is frequently encountered and promotes proliferation, survival, metastasis and angiogenesis in hepatocellular carcinoma (HCC). Here, we have investigated whether emodin mediates its effect through interference with the STAT3 activation pathway in HCC.
  
  
  METHODS
  The effect of emodin on STAT3 activation, associated protein kinases and apoptosis was investigated using various HCC cell lines. Additionally, we also used a predictive tumour technology to analyse the effects of emodin . The in vivo effects of emodin were assessed in an orthotopic mouse model of HCC.
  
  
  RESULTS
  Emodin suppressed STAT3 activation in a dose- and time-dependent manner in HCC cells, mediated by the modulation of activation of upstream kinases c-Src, JAK1 and JAK2. Vanadate treatment reversed emodin-induced down-regulation of STAT3, suggesting the involvement of a tyrosine phosphatase and emodin induced the expression of the tyrosine phosphatase SHP-1 that correlated with the down-regulation of constitutive STAT3 activation. Interestingly, silencing of the SHP-1 gene by siRNA abolished the ability of emodin to inhibit STAT3 activation. Finally, when administered i.p., emodin inhibited the growth of human HCC orthotopic tumours in male athymic nu/nu mice and STAT3 activation in tumour tissues.
  
  
  CONCLUSIONS
  Emodin mediated its effects predominantly through inhibition of the STAT3 signalling cascade and thus has a particular potential for the treatment of cancers expressing constitutively activated STAT3.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Molecular Toxicology Lab, Department of Biotechnology, Bharathiar University, Coimbatore, India.
authors.forename: Aruljothi
authors.initials: A
authors.lastname: Subramaniam
authors.forename: Muthu K
authors.initials: MK
authors.lastname: Shanmugam
authors.forename: Tina H
authors.initials: TH
authors.lastname: Ong
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Ekambaram
authors.initials: E
authors.lastname: Perumal
authors.forename: Luxi
authors.initials: L
authors.lastname: Chen
authors.forename: Shireen
authors.initials: S
authors.lastname: Vali
authors.forename: Taher
authors.initials: T
authors.lastname: Abbasi
authors.forename: Shweta
authors.initials: S
authors.lastname: Kapoor
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
authors.forename: Alan Prem
authors.initials: AP
authors.lastname: Kumar
authors.forename: Kam M
authors.initials: KM
authors.lastname: Hui
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004642:Emodin / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D053613:Janus Kinase 1 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C508600:IL6 protein, human; D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D004642:Emodin
keywords: STAT3; apoptosis; emodin; hepatocellular carcinoma; proliferation