title: γ-Tocotrienol is a novel inhibitor of constitutive and inducible STAT3 signalling pathway in human hepatocellular carcinoma: potential role as an antiproliferative, pro-apoptotic and chemosensitizing agent.
abstract: OBJECTIVE
  Activation of signal transducer and activator of transcription 3 (STAT3) play a critical role in the survival, proliferation, angiogenesis and chemoresistance of tumour cells. Thus, agents that suppress STAT3 phosphorylation have potential as cancer therapies. In the present study, we investigated whether the apoptotic, antiproliferative and chemosensitizing effects of γ-tocotrienol are associated with its ability to suppress STAT3 activation in hepatocellular carcinoma (HCC).
  
  
  METHODS
  The effect of γ-tocotrienol on STAT3 activation, associated protein kinases and phosphatase, STAT3-regulated gene products, cellular proliferation and apoptosis in HCC cells was investigated.
  
  
  RESULTS
  γ-Tocotrienol inhibited both the constitutive and inducible activation of STAT3 with minimum effect on STAT5. γ-Tocotrienol also inhibited the activation of Src, JAK1 and JAK2 implicated in STAT3 activation. Pervanadate reversed the γ-tocotrienol-induced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that γ-tocotrienol induced the expression of the tyrosine phosphatase SHP-1 and deletion of the SHP-1 gene by small interfering RNA abolished the ability of γ-tocotrienol to inhibit STAT3 activation. γ-Tocotrienol also down-regulated the expression of STAT3-regulated gene products, including cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1 and vascular endothelial growth factor. Finally, γ-tocotrienol inhibited proliferation, induced apoptosis and significantly potentiated the apoptotic effects of chemotherapeutic drugs (paclitaxel and doxorubicin) used for the treatment of HCC.
  
  
  CONCLUSIONS
  Overall, these results suggest that γ-tocotrienol is a novel blocker of the STAT3 activation pathway, with a potential role in future therapies for HCC and other cancers.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Peramaiyan
authors.initials: P
authors.lastname: Rajendran
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Kanjoormana Aryan
authors.initials: KA
authors.lastname: Manu
authors.forename: Muthu K
authors.initials: MK
authors.lastname: Shanmugam
authors.forename: Ser Yue
authors.initials: SY
authors.lastname: Loo
authors.forename: Alan Prem
authors.initials: AP
authors.lastname: Kumar
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004789:Enzyme Activation; D004790:Enzyme Induction; D017930:Genes, Reporter; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D008113:Liver Neoplasms; D016328:NF-kappa B / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002839:Chromans; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014810:Vitamin E; C013649:plastochromanol 8; D004317:Doxorubicin; D053612:Janus Kinases; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D017027:Protein Tyrosine Phosphatases; D017239:Paclitaxel