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Calmodulin Binding to Death Receptor 5-mediated Death-Inducing Signaling Complex in Breast Cancer Cells

Romone M Fancy1, Harrison Kim2, Tong Zhou3

  • 1Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham 35294, Alabama.

Journal of Cellular Biochemistry
|January 17, 2017
PubMed

Insights

Calmodulin (CaM) binds to the death-inducing signaling complex (DISC) in a calcium-dependent manner, regulating apoptosis in breast cancer cells treated with the TRA-8 antibody. This finding identifies CaM as a key regulator of DR5-mediated DISC formation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Activation of death receptor-5 (DR5) initiates apoptosis via DISC formation.
  • The DR5-specific antibody TRA-8 shows potent anti-cancer activity.
  • Calmodulin (CaM) is overexpressed in breast cancer and influences DR5-mediated apoptosis, but its precise role is unclear.

Purpose of the Study:

  • To investigate the mechanism of CaM in regulating DR5-mediated apoptotic signaling.
  • To characterize CaM binding to the DISC in TRA-8-sensitive breast cancer cells.

Main Methods:

  • Co-immunoprecipitation assays to detect protein interactions.
  • Fluorescence microscopic imaging to visualize CaM recruitment.
  • Caspase signaling analysis and cell viability assays to assess apoptosis.
  • Utilized CaM antagonist trifluoperazine (TFP) and Ca2+ chelator EGTA.

Main Results:

  • CaM was recruited to the DR5-mediated DISC in a calcium-dependent manner upon DR5 activation.
  • The CaM antagonist TFP inhibited CaM recruitment, DISC formation, and DR5 oligomerization.
  • TFP and EGTA impaired TRA-8-induced caspase signaling and reduced cancer cell cytotoxicity.
  • CaM binding to the DISC was confirmed to be crucial for TRA-8-induced apoptosis.

Conclusions:

  • Calmodulin binds to the DR5-mediated DISC in a calcium-dependent manner.
  • CaM acts as a key regulator of DISC formation and subsequent apoptosis in breast cancer.
  • These findings highlight a novel mechanism in DR5-mediated apoptosis and suggest potential therapeutic targets.
Keywords:
APOPTOSISBREAST CANCER CELLSCALMODULINDEATH RECEPTOR 5DISCDR5 OLIGOMERIZATION

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