Intracellularly transported adenosine induces apoptosis in HuH-7 human hepatoma cells by downregulating c-FLIP expression causing caspase-3/-8 activation

Biochem Pharmacol. 2007 May 15;73(10):1665-75. doi: 10.1016/j.bcp.2007.01.020. Epub 2007 Jan 18.


Extracellular adenosine induced apoptosis of HuH-7 cells, a Fas-deficient human hepatoma cell line. The adenosine action was inhibited by dipyridamole, an adenosine transporter inhibitor, or 5'-amino-5'-deoxyadenosine, an inhibitor of adenosine kinase to convert from adenosine to AMP, but it was not affected by inhibitors for adenosine A(1), A(2a), A(2b), and A(3) adenosine receptors. Adenosine activated caspase-3 and -8, but not caspase-9, in HuH-7 cells, and the activation was abolished by dipyridamole. In the real-time RT-PCR and Western blot analysis, extracellular adenosine downregulated mRNA and protein levels for c-FLIP, and the effect was suppressed by dipyridamole. Furthermore, overexpression of c-FLIP short in HuH-7 cells inhibited adenosine-induced caspase-8 activity. Taken together, these results suggest that intracellularly transported adenosine, perhaps converted AMP as the ensuing event, activates caspase-8 and the downstream effector caspase caspase-3 by neutralizing caspase-8 inhibition due to c-FLIP as a consequence of decreased c-FLIP expression, leading to apoptosis. This extends our understanding of adenosine-induced molecular apoptotic pathways.

MeSH terms

  • Adenosine / metabolism*
  • Apoptosis / physiology*
  • Biological Transport / physiology*
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
  • Carcinoma, Hepatocellular / pathology*
  • Caspase 3 / metabolism*
  • Caspase 8 / metabolism*
  • Down-Regulation
  • Enzyme Activation
  • Gene Expression
  • Humans
  • Liver Neoplasms / pathology
  • Tumor Cells, Cultured


  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Caspase 3
  • Caspase 8
  • Adenosine