Activation of caspase-8 in transforming growth factor-beta-induced apoptosis of human hepatoma cells

Hepatology. 1999 Nov;30(5):1215-22. doi: 10.1002/hep.510300503.


Transforming growth factor-beta1 (TGF-beta1) has been shown to induce apoptosis in normal or transformed hepatocytes. To elucidate the biochemical pathways leading to apoptosis induced by TGF-beta1 in human hepatoma cells (HuH-7), we examined the expression of Bcl-2-related proteins and X-chromosome-linked inhibitor of apoptosis (XIAP), and activation of the caspase cascade following TGF-beta1 treatment. Bcl-xL expression began to decline at 12 hours after TGF-beta1 treatment and progressively decreased to very low levels in a time-dependent manner. Bax expression showed a little change throughout the experiment. On the other hand, activation of caspase-8 was clearly observed at 36 hours after TGF-beta1 treatment, followed by activation of caspase-9, and caspase-3 was activated at 48 hours after treatment at which time apoptosis of HuH-7 cells was observed. TGF-beta1 significantly decreased XIAP expression in HuH-7 cells. Addition of an inhibitor of caspase-8 or caspase-3 (IETD-FMK or DEVD-CHO) markedly inhibited TGF-beta1-induced apoptosis of HuH-7 cells. Fas/Fas ligand (FasL) interactions in HuH-7 cells were not involved in the apoptotic process. Furthermore, epidermal growth factor (EGF) also completely inhibited TGF-beta1-induced apoptosis of HuH-7 cells by inhibiting activation of the caspase cascade. Our results suggested that activation of caspase-3 initiated through caspase-8 activation is involved in the apoptotic process induced by TGF-beta1 in HuH-7 cells. Our results also showed that down-regulation of the expression of Bcl-xL and XIAP by TGF-beta1 may facilitate activation of caspase-3 in these cells.

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Carcinoma, Hepatocellular
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspase Inhibitors
  • Caspases / metabolism*
  • Cell Division / drug effects*
  • Cysteine Proteinase Inhibitors / pharmacology
  • Enzyme Activation / drug effects
  • Epidermal Growth Factor / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • In Situ Nick-End Labeling
  • Kinetics
  • Liver Neoplasms
  • Oligopeptides / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Time Factors
  • Transforming Growth Factor beta / toxicity*
  • Tumor Cells, Cultured
  • bcl-X Protein
  • fas Receptor / physiology


  • BCL2L1 protein, human
  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • Oligopeptides
  • Proto-Oncogene Proteins c-bcl-2
  • Transforming Growth Factor beta
  • aspartyl-glutamyl-valyl-aspartal
  • bcl-X Protein
  • fas Receptor
  • Epidermal Growth Factor
  • CASP3 protein, human
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases