Cell Biology and Toxicology

, Volume 26, Issue 4, pp 319–330

Adenosine-induced caspase-3 activation by tuning Bcl-XL/DIABLO/IAP expression in HuH-7 human hepatoma cells

  • Dongqin Yang
  • Takahiro Yaguchi
  • Takashi Nakano
  • Tomoyuki Nishizaki

DOI: 10.1007/s10565-009-9145-7

Cite this article as:
Yang, D., Yaguchi, T., Nakano, T. et al. Cell Biol Toxicol (2010) 26: 319. doi:10.1007/s10565-009-9145-7


Extracellular adenosine disrupted mitochondrial membrane potentials in HuH-7 cells, a Fas-deficient human hepatoma cell line, and the effect was inhibited by the adenosine transporter inhibitor dipyridamole or by overexpressing Bcl-XL. Adenosine downregulated the expression of mRNAs and proteins for Bcl-XL and inhibitor of apoptosis protein 2 (IAP2) to directly inhibit caspase-3, -7, and -9, but it otherwise upregulated the expression of mRNA and protein for DIABLO, an inhibitor of IAPs. Those adenosine effects were attenuated by dipyridamole. Caspase-3 and -8 were implicated in adenosine-induced HuH-7 cell death, and adenosine actually activated caspase-3 without caspase-9 activation. The caspase-3 activation was inhibited by overexpressing Bcl-XL or IAP2. Taken together, the results of the present study indicate that intracellularly transported adenosine activates caspase-3 by neutralizing caspase-3 inhibition due to IAP as a result of decreased IAP2 expression and reduced IAP activity in response to increased DIABLO expression and perhaps DIABLO release from damaged mitochondria, in addition to caspase-8 activation. This represents further insight into adenosine-induced HuH-7 cell apoptotic pathway.


Adenosine HuH-7 cell Bcl-XL DIABLO Inhibitor of apoptosis protein 



Inhibitor of apoptosis protein


Fas-associated death domain protein


FADD-like interleukin-1β-converting enzyme inhibitory protein


Apoptosis-inducing factor


Apoptosis proteases activating factor-1


Dulbecco's modified Eagle's medium


3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide


Phosphate-buffered saline


Reverse transcription-polymerase chain reaction


Sodium dodecyl sulfate polyacrylamide gel electrophoresis


Analysis of variance

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Dongqin Yang
    • 1
  • Takahiro Yaguchi
    • 1
  • Takashi Nakano
    • 2
  • Tomoyuki Nishizaki
    • 1
  1. 1.Division of Bioinformation, Department of PhysiologyHyogo College of MedicineNishinomiyaJapan
  2. 2.Department of Thoracic OncologyHyogo College of MedicineNishinomiyaJapan
  3. 3.Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological SciencesChinese Academy of SciencesShanghaiChina

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