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E-cadherin couples death receptors to the cytoskeleton to regulate apoptosis

Min Lu1, Scot Marsters1, Xiaofen Ye1

  • 1Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

Molecular Cell
|June 3, 2014
PubMed

Insights

Epithelial-to-mesenchymal transition (EMT) suppresses apoptosis by reducing E-cadherin. This protein is crucial for E-cadherin-mediated apoptosis signaling via death receptors DR4/DR5, impacting cancer therapy.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Epithelial-to-mesenchymal transition (EMT) is vital for tissue development but its role in suppressing apoptosis in cancer is not fully understood.
  • Apoptosis, or programmed cell death, is a critical process that is often dysregulated in cancer.
  • Death receptors like DR4 and DR5 initiate apoptotic signaling pathways.

Purpose of the Study:

  • To elucidate the mechanisms by which EMT suppresses apoptosis.
  • To investigate the role of E-cadherin in regulating apoptosis signaling through death receptors.
  • To explore the potential therapeutic implications of targeting EMT-mediated apoptosis resistance.

Main Methods:

  • Investigated the effect of EMT on apoptosis signaling via DR4 and DR5.
  • Examined the role of E-cadherin, α-catenin, and actin cytoskeleton in apoptosis.
  • Analyzed E-cadherin binding to DR4/DR5 and its effect on death-inducing signaling complex (DISC) formation.
  • Assessed caspase-8 activation and apoptosis sensitivity in cancer cell lines with varying E-cadherin levels.

Main Results:

  • EMT selectively attenuated apoptosis signaling through death receptors DR4 and DR5.
  • Loss of E-cadherin mimicked EMT's effect on apoptosis; E-cadherin engagement promoted DR4/DR5 signaling.
  • E-cadherin directly binds to ligated DR4/DR5, enhancing receptor clustering and DISC assembly.
  • EMT inhibited DR4/DR5-mediated DISC formation and caspase-8 activation.
  • Epithelial cancer cells with higher E-cadherin showed increased sensitivity to DR4/DR5-induced apoptosis.

Conclusions:

  • E-cadherin is a key regulator of DR4/DR5-mediated apoptosis, and its loss during EMT contributes to apoptosis resistance in cancer.
  • Targeting E-cadherin-mediated signaling pathways could offer novel therapeutic strategies for overcoming apoptosis resistance in epithelial cancers.
  • Understanding the interplay between EMT, E-cadherin, and apoptosis is crucial for advancing cancer treatment and maintaining tissue homeostasis.

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