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Pigment epithelial-derived factor inhibits c-FLIP expression and assists ciglitazone-induced apoptosis in

Li-Ju Lai1, Tsung-Chuan Ho

  • 1Department of Ophthalmology, Chang Gang Memorial Hospital, Chia-Yi County, Taiwan, Republic of China.

Anticancer Research
|April 22, 2011
PubMed
Abstract

Insights

Pigment epithelial-derived factor (PEDF) reduces cellular FLICE-inhibitory protein (c-FLIP) in hepatoma cells via p38 kinase signaling. This finding suggests PEDF enhances apoptotic activity in liver cancer cells.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Pigment epithelial-derived factor (PEDF) exhibits antiangiogenic properties partly by suppressing cellular FADD-like IL-1β-converting enzyme (FLICE)/caspase-8-inhibitory protein (c-FLIP) in endothelial cells.
  • c-Jun NH(2)-terminal kinases (JNKs) are known regulators of c-FLIP expression in endothelial cells, but PEDF's effects on other cell types are not well understood.

Purpose of the Study:

  • To investigate the effect of PEDF on c-FLIP expression in hepatoma cells.
  • To elucidate the signaling pathways involved in PEDF-mediated c-FLIP regulation in hepatoma cells.
  • To determine if PEDF influences the apoptotic response of hepatoma cells.

Main Methods:

  • Semi-quantitative reverse transcriptase (RT)-PCR and immunoblotting were employed to assess c-FLIP expression.
  • Pharmacological inhibitors targeting specific signaling pathways were utilized to examine PEDF signaling involvement.
  • Hepatoma cell line SK-Hep-1 was used to study PEDF effects on c-FLIP and apoptosis.

Main Results:

  • PEDF was found to down-regulate c-FLIP expression in SK-Hep-1 hepatoma cells.
  • PEDF induced p38 kinase phosphorylation in SK-Hep-1 cells, and this effect on c-FLIP was abrogated by a p38 kinase inhibitor.
  • PEDF pretreatment sensitized SK-Hep-1 cells to ciglitazone-induced procaspase-8 cleavage and apoptosis, an effect not mediated by JNK inhibition.

Conclusions:

  • PEDF-induced p38 signaling is responsible for the down-regulation of c-FLIP in SK-Hep-1 cells.
  • PEDF demonstrates a novel role in modulating apoptotic inducible activity within hepatoma cells.
  • These findings suggest a potential therapeutic application of PEDF in liver cancer treatment by enhancing apoptosis.

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