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

Y Shima1, K Nakao, T Nakashima

  • 1Department of Clinical Pharmacology, Nagasaki University School of Medicine, Nagasaki, Japan.

Hepatology (Baltimore, Md.)
|October 26, 1999
PubMed

Insights

Transforming growth factor-beta1 (TGF-beta1) induces apoptosis in human hepatoma cells by activating caspase-3, which is facilitated by decreased Bcl-xL and XIAP expression. Epidermal growth factor (EGF) inhibits this TGF-beta1-induced cell death.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Hepatology

Background:

  • Transforming growth factor-beta1 (TGF-beta1) is known to induce apoptosis in hepatocytes.
  • Understanding the specific molecular mechanisms is crucial for therapeutic development in liver cancer.

Purpose of the Study:

  • To elucidate the biochemical pathways of TGF-beta1-induced apoptosis in human hepatoma (HuH-7) cells.
  • To investigate the roles of Bcl-2 family proteins, XIAP, and the caspase cascade.

Main Methods:

  • HuH-7 cells were treated with TGF-beta1.
  • Expression of Bcl-xL, Bax, and XIAP was analyzed over time.
  • Caspase activation (caspase-8, -9, -3) was assessed.
  • Apoptosis was quantified, and the effects of caspase inhibitors and EGF were evaluated.

Main Results:

  • TGF-beta1 decreased Bcl-xL and XIAP expression in a time-dependent manner.
  • Bax expression remained relatively unchanged.
  • Caspase-8 activation preceded caspase-9 and caspase-3 activation, correlating with observed apoptosis.
  • Caspase inhibitors and EGF significantly blocked TGF-beta1-induced apoptosis.
  • Fas/FasL signaling was not involved.

Conclusions:

  • TGF-beta1 induces apoptosis in HuH-7 cells primarily through caspase-8 and caspase-3 activation.
  • Down-regulation of Bcl-xL and XIAP by TGF-beta1 facilitates caspase-3 activation.
  • EGF inhibits TGF-beta1-induced apoptosis by suppressing caspase cascade activation.

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