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Downregulation of Bid is associated with PKCepsilon-mediated TRAIL resistance

U Sivaprasad1, E Shankar, A Basu

  • 1Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.

Cell Death and Differentiation
|December 23, 2006
PubMed

Insights

Protein kinase C-epsilon (PKCepsilon) confers resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in breast cancer cells. It regulates Bcl-2 and Bid proteins, impacting cell death pathways and offering potential therapeutic targets.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells, but resistance limits its efficacy.
  • Protein kinase C-epsilon (PKCepsilon) has been identified as an antiapoptotic protein in MCF-7 breast cancer cells.

Purpose of the Study:

  • To elucidate the mechanisms by which PKCepsilon contributes to TRAIL resistance in cancer cells.
  • To investigate the role of PKCepsilon in regulating key apoptotic proteins and signaling pathways involved in TRAIL-induced cell death.

Main Methods:

  • Overexpression and knockdown/inhibition of PKCepsilon in MCF-7 cells.
  • Analysis of caspase activation (caspase-8, -9), cytochrome c release, and cell death.
  • Assessment of Bcl-2, Bid, and Bax protein and mRNA levels.
  • Use of small interfering RNA (siRNA) to modulate Bcl-2 and Bid expression.

Main Results:

  • PKCepsilon overexpression inhibited TRAIL-induced caspase activation, cytochrome c release, and cell death.
  • PKCepsilon overexpression increased Bcl-2 levels and decreased Bid levels, while not affecting Bax.
  • PKCepsilon knockdown/inhibition enhanced TRAIL sensitivity.
  • Bcl-2 knockdown reversed TRAIL resistance in PKCepsilon-overexpressing cells, whereas Bid depletion enhanced TRAIL resistance.

Conclusions:

  • PKCepsilon mediates TRAIL resistance in MCF-7 cells by acting upstream of the mitochondria.
  • The antiapoptotic effects of PKCepsilon involve the regulation of Bcl-2 and Bid protein levels.
  • Targeting PKCepsilon or its downstream effectors (Bcl-2, Bid) may overcome TRAIL resistance in breast cancer.

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