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Transforming growth factor beta1 induces apoptosis by suppressing FLICE-like inhibitory protein in DU145 prostate

Kiwon S Yoo1, Kent L Nastiuk, John J Krolewski

  • 1Department of Pathology and Laboratory Medicine, Medical Sciences I D450, University of California, Irvine, Irvine, CA 92697-4800, USA.

International Journal of Cancer
|December 3, 2008
PubMed

Insights

Transforming growth factor beta (TGFbeta) induces prostate cancer cell death by downregulating the caspase inhibitor FLIP. Silencing FLIP alone also causes apoptosis, confirming its role in TGFbeta-mediated cell death.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Transforming growth factor beta (TGFbeta) is a key mediator of apoptosis in prostate epithelial cells.
  • Castration in rodents stimulates stromal TGFbeta production, leading to epithelial cell death.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying TGFbeta-induced apoptosis in prostate cancer cells.
  • To identify potential mediators of this cell death pathway using a human prostate epithelial cell line.

Main Methods:

  • Utilized DU145 cells, a human prostate epithelial cell line, cultured at low density in low-mitogen media.
  • Administered TGFbeta1 and analyzed changes in FLICE-like inhibitory protein (FLIP) expression at mRNA and protein levels.
  • Employed small interfering RNA (siRNA) to silence FLIP expression and inhibit caspase-8.

Main Results:

  • TGFbeta1 treatment induced apoptosis in DU145 cells.
  • TGFbeta1 downregulated both mRNA and protein expression of FLIP prior to cell death.
  • siRNA-mediated silencing of FLIP resulted in apoptosis, supporting its role as a cell death inhibitor.
  • Inhibition of caspase-8 partially rescued cells from TGFbeta1-induced apoptosis.

Conclusions:

  • FLIP downregulation is a critical step in TGFbeta1-mediated apoptosis of prostate epithelial cells.
  • Death receptor signaling components, including caspase-8, are involved in TGFbeta-mediated cell death.
  • FLIP acts as a crucial inhibitor of apoptosis in this context.

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