Jak inhibitor induces S phase cell-cycle arrest and augments TRAIL-induced apoptosis in human hepatocellular carcinoma cells

Biochem Biophys Res Commun. 2007 Nov 23;363(3):738-44. doi: 10.1016/j.bbrc.2007.09.049. Epub 2007 Sep 21.


Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in various cancers and plays a crucial role in oncogensis, including the activation of genes encoding apoptosis inhibitors and cell-cycle regulators. We investigated the biological significance of the Janus kinase (Jak)-STAT pathway in human hepatocellular carcinoma (HCC). Constitutive activation of STAT3 was seen in 49.4% of human HCC specimens and in HCC cell lines. Jak inhibitor AG490 inhibited activation of STAT3 and markedly reduced cell viability without significant apoptosis. AG490 also induced S phase cell-cycle arrest with down-regulation of cyclin D1, A, E and up-regulation of p21, p27, phospho-Chk2. AG490 also inhibited caspase inhibitory proteins, such as XIAP and survivin, and augmented TRAIL-induced apoptosis. Our study suggests that the Jak-STAT pathway plays an important role in cell-cycle progression and resistance to apoptosis. Inhibition of the Jak-STAT pathway may thus be a therapeutic target for HCC.

MeSH terms

  • Apoptosis / drug effects*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / physiopathology
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Flow Cytometry
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Janus Kinases / antagonists & inhibitors*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Liver Neoplasms / physiopathology
  • Phosphorylation / drug effects
  • S Phase / drug effects*
  • STAT3 Transcription Factor / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*
  • Tyrphostins / pharmacology*


  • Enzyme Inhibitors
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • TNF-Related Apoptosis-Inducing Ligand
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • Janus Kinases