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Protein kinase Cδ and caspase-3 modulate TRAIL-induced apoptosis in breast tumor cells

Shuping Yin1, Seema Sethi, Kaladhar B Reddy

  • 1Department of Pathology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, Michigan 48201, USA.

Journal of Cellular Biochemistry
|July 29, 2010
PubMed

Insights

Overexpression of protein kinase C delta (PKCδ) prevents TRAIL-induced apoptosis in breast cancer by inhibiting caspase-8 activation. Inhibiting PKCδ or its cleavage by caspase-3 restores apoptosis, suggesting combination therapy for tumors.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Protein kinase C delta (PKCδ) plays a role in cell apoptosis.
  • TRAIL (TNF-related apoptosis-inducing ligand) induces apoptosis in cancer cells.
  • The precise mechanism of PKCδ in regulating TRAIL-induced apoptosis is not fully understood.

Purpose of the Study:

  • To investigate the role of PKCδ in TRAIL-induced apoptosis in breast tumor cells.
  • To elucidate the regulatory mechanism of PKCδ in this process.
  • To explore potential therapeutic strategies targeting PKCδ in breast cancer.

Main Methods:

  • Overexpression of PKCδ in MCF-7 breast cancer cells.
  • Inhibition of PKCδ using rottlerin and siRNA.
  • Development of cell lines expressing wild-type or cleavage-resistant PKCδ mutants.
  • Assessment of caspase-8 activation and apoptosis induction.

Main Results:

  • PKCδ overexpression significantly inhibited TRAIL-induced apoptosis in MCF-7 cells.
  • PKCδ was found to inhibit caspase-8 activation, a key step in apoptosis.
  • Inhibition of PKCδ via rottlerin, siRNA, or caspase-3 cleavage sensitized cells to TRAIL-induced apoptosis.
  • Cleavage-resistant PKCδ mutant cells showed greater inhibition of TRAIL-induced apoptosis compared to wild-type.

Conclusions:

  • PKCδ overexpression inhibits TRAIL-induced apoptosis by blocking caspase-8 activation.
  • PKCδ cleavage by caspase-3 is a mechanism to overcome its anti-apoptotic effect.
  • Combination therapy with PKCδ inhibitors and TRAIL may be a promising strategy for treating PKCδ-overexpressing breast tumors.

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