title: Inhibition of STAT3 dimerization and acetylation by garcinol suppresses the growth of human hepatocellular carcinoma in vitro and in vivo.
abstract: BACKGROUND
  Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been linked with proliferation, survival, invasion and angiogenesis of a variety of human cancer cells, including hepatocellular carcinoma (HCC). Thus, novel agents that can suppress STAT3 activation have potential for both prevention and treatment of HCC. Here we report, garcinol, a polyisoprenylated benzophenone, could suppress STAT3 activation in HCC cell lines and in xenografted tumor of HCC in nude mice model.
  
  
  METHODS
  Different HCC cell lines have been treated with garcinol and the inhibition of STAT3 activation, dimerization and acetylation have been checked by immunoblotting, immuno-fluorescence, and DNA binding assays. Xenografted tumor model has been generated in nude mice using HCC cell line and effect of garcinol in the inhibition of tumor growth has been investigated.
  
  
  RESULTS
  Garcinol could inhibit both constitutive and interleukin (IL-6) inducible STAT3 activation in HCC cells. Computational modeling showed that garcinol could bind to the SH2 domain of STAT3 and suppress its dimerization in vitro. Being an acetyltransferase inhibitor, garcinol also inhibits STAT3 acetylation and thus impairs its DNA binding ability. The inhibition of STAT3 activation by garcinol led to the suppression of expression of various genes involved in proliferation, survival, and angiogenesis. It also suppressed proliferation and induced substantial apoptosis in HCC cells. Remarkably, garcinol inhibited the growth of human HCC xenograft tumors in athymic nu/nu mice, through the inhibition of STAT3 activation.
  
  
  CONCLUSIONS
  Overall, our results suggest that garcinol exerts its anti-proliferative and pro-apoptotic effects through suppression of STAT3 signaling in HCC both in vitro and in vivo.
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
authors.forename: Snehajyoti
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Peramaiyan
authors.initials: P
authors.lastname: Rajendran
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Muthu K
authors.initials: MK
authors.lastname: Shanmugam
authors.forename: Kwong Fai
authors.initials: KF
authors.lastname: Wong
authors.forename: Alan Prem
authors.initials: AP
authors.lastname: Kumar
authors.forename: Parijat
authors.initials: P
authors.lastname: Senapati
authors.forename: Amit K
authors.initials: AK
authors.lastname: Behera
authors.forename: Kam Man
authors.initials: KM
authors.lastname: Hui
authors.forename: Jeelan
authors.initials: J
authors.lastname: Basha
authors.forename: Nagashayana
authors.initials: N
authors.lastname: Natesh
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore. dr.johnluk@gmail.com.
authors.forename: John M
authors.initials: JM
authors.lastname: Luk
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Kundu
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019281:Dimerization; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013729:Terpenes / Q000008:administration & dosage*
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013729:Terpenes; C054597:garcinol