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BCL2 and CASP8 regulation by NF-kappaB differentially affect mitochondrial function and cell fate in

Ruchi Nehra1, Rebecca B Riggins, Ayesha N Shajahan

  • 1Department of Oncology, Georgetown University School of Medicine, Washington, DC 20057, USA.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|February 16, 2010
PubMed

Insights

Inhibiting NF-kappaB (nuclear factor kappa B) restores tamoxifen sensitivity in resistant ER-positive breast cancer cells. This approach may offer a new therapeutic strategy for managing breast cancer by targeting molecular signaling pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • Endocrine therapy resistance is a significant challenge in managing ER-positive breast cancer.
  • Understanding the molecular mechanisms underlying tamoxifen resistance is crucial for developing effective treatments.

Purpose of the Study:

  • To investigate the role of NF-kappaB (nuclear factor kappa B) signaling in tamoxifen resistance.
  • To explore the potential of inhibiting NF-kappaB to restore sensitivity to 4-hydroxytamoxifen (4HT) in resistant breast cancer cells.

Main Methods:

  • Overexpression of a mutant IkappaB (IkappaBSR) and treatment with parthenolide, a small-molecule inhibitor of NF-kappaB.
  • Assessment of cell sensitivity to 4HT, cell cycle distribution, autophagy markers (p62/SQSTM1, LC3), BCL2 expression, mitochondrial membrane permeability, and caspase-dependent apoptosis.
  • Use of a caspase 8 (CASP8)-specific inhibitor to evaluate the role of CASP8 activity.

Main Results:

  • NF-kappaB inhibition synergistically restored 4HT sensitivity in resistant MCF7/RR and MCF7/LCC9 cells and sensitized control cells.
  • These effects were independent of cell cycle or autophagy modulation.
  • NF-kappaB inhibition restored 4HT's ability to decrease BCL2, increase mitochondrial membrane permeability, and induce apoptosis via CASP8 activation.

Conclusions:

  • Increased NF-kappaB activation contributes to tamoxifen resistance by modulating CASP8 activity.
  • Targeting NF-kappaB signaling, potentially with parthenolide and tamoxifen combination therapy, shows promise for treating ER-positive breast cancers resistant to endocrine therapies.

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