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Tumor necrosis factor induces apoptosis in hepatoma cells by increasing Ca(2+) release from the endoplasmic reticulum

Byung-Chul Kim1, Heung-Tae Kim, Mizuko Mamura

  • 1Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

The Journal of Biological Chemistry
|June 22, 2002
PubMed

Insights

Tumor necrosis factor (TNF) triggers apoptosis in liver cells by releasing calcium from the ER and reducing Bcl-2. Dantrolene and Bcl-2 expression block this TNF-induced cell death.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Tumor necrosis factor (TNF) is a key regulator of apoptosis.
  • The canonical TNF-induced apoptotic pathway involves TNFR1, FADD, and caspase-8.
  • The precise mechanisms of TNF-induced apoptosis in specific cell types require further elucidation.

Purpose of the Study:

  • To investigate the mechanism of TNF-induced apoptosis in FaO rat hepatoma cells.
  • To identify the specific caspases activated by TNF in this cellular model.
  • To examine the role of Bcl-2 family proteins and calcium signaling in TNF-induced apoptosis.

Main Methods:

  • FaO rat hepatoma cells were treated with TNF.
  • Apoptosis levels were quantified.
  • Caspase activation (caspase-3, -8, -10, -12), Bcl-2 family protein expression, and intracellular calcium (Ca2+) release from the endoplasmic reticulum (ER) were assessed.
  • The effects of dantrolene and Bcl-2 overexpression were evaluated.

Main Results:

  • TNF treatment significantly increased apoptosis in FaO cells.
  • TNF activated caspase-3, -10, and -12, but not caspase-8.
  • TNF suppressed Bcl-2 expression and induced Ca2+ release from the ER.
  • Dantrolene inhibited TNF's effect on Bcl-2 and Ca2+ release.
  • Bcl-2 expression blocked TNF-induced apoptosis and Ca2+ release.

Conclusions:

  • TNF induces apoptosis in FaO rat hepatoma cells via a non-canonical pathway.
  • This mechanism involves Ca2+ release from the ER and suppression of Bcl-2 expression.
  • Bcl-2 plays a critical role in protecting cells against TNF-induced apoptosis.

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