Abrogation of constitutive STAT3 activity sensitizes human hepatoma cells to TRAIL-mediated apoptosis

J Hepatol. 2007 Oct;47(4):546-55. doi: 10.1016/j.jhep.2007.04.017. Epub 2007 Jun 6.


Background/aims: Signal transducer and activator of transcription 3 (STAT3) is constitutively activated and regulates cell growth and survival of various cancer cells. We investigated the anti-tumor effect of AG490, a Janus kinase 2 specific inhibitor, inhuman hepatoma cells.

Methods: Effects of AG490 on STAT3 activation, on cell-growth and survival, and on the expression of cell-cycle- and apoptosis-related proteins were evaluated in Huh-1, Huh-7, HepG2 and Hep3B cells. Next, whether AG490 renders hepatoma cells susceptible to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was examined in vitro and in vivo.

Results: Constitutively activated STAT3 through tyrosine phosphorylation was detected in all hepatoma cells. AG490 inhibited the phosphorylation of STAT3 and its activity. AG490 induced cell cycle arrest in Huh-1, Huh-7 and HepG2 through cyclin D1 downregulation, and induced marked apoptosis in Hep3B. AG490 downregulated at least one of the anti-apoptotic proteins, Bcl-xL, survivin or XIAP in all hepatoma cells. AG490 sensitized Huh-1, Huh-7 and HepG2 to TRAIL-induced apoptosis in vitro. Intraperitoneal injection of AG490, the combination of AG490 and TRAIL more greatly, repressed the growth of subcutaneous Huh-7 tumors in athymic mice.

Conclusions: Abrogation of constitutive activation of STAT3 by AG490 enhances the anti-tumor activity of TRAIL against human hepatoma cells.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Carcinoma, Hepatocellular
  • Cell Line, Tumor
  • Cyclin D1 / antagonists & inhibitors
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors
  • Liver Neoplasms / metabolism*
  • Mice
  • Mice, Nude
  • Phosphorylation / drug effects
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • STAT3 Transcription Factor / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*
  • Tyrphostins / pharmacology*
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • TNF-Related Apoptosis-Inducing Ligand
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • Cyclin D1
  • Janus Kinase 2