A soluble truncated cadherin induces breast cancer cell apoptosis and growth inhibition

Xiao-Yu Shi1, He Lu, Wen-Lin Li

  • 1INSERM, Institut Universitaire d'Hématologie, U553, Université Paris 7, 75010 Paris, France.

Abstract

Insights

A soluble truncated cadherin (CED1-4) acts as an effective apoptotic inducer and growth inhibitor in breast cancer cells. This molecule down-regulates integrin beta1 and blocks c-fos expression, contributing to its anti-cancer effects.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Vascular Endothelial Cadherin (VE-cadherin) plays a crucial role in endothelial cell-cell adhesion.
  • Truncated forms of cadherins may possess novel biological functions.
  • Understanding the characteristics of soluble cadherin fragments is important for therapeutic development.

Purpose of the Study:

  • To characterize a soluble truncated cadherin fragment (CED1-4) containing VE-cadherin extracellular domain repeats 1-4 and a signal peptide.
  • To investigate the functional role of CED1-4 as a soluble molecule in breast cancer cells.

Main Methods:

  • Construction of a pMSCV/CED1-4 retroviral vector.
  • Transfection of MDA-MB435 human breast cancer cells with ReCED1-4 or ReEmpty retroviruses.
  • Analysis of CED1-4 expression using RT-PCR and Western blot.
  • In vitro and in vivo proliferation assays.
  • Apoptosis assays (Annexin V, TUNEL, caspase 3).
  • Detection of integrin beta1 and c-fos mRNA expression.

Main Results:

  • Soluble CED1-4 (484 amino acids including a 27-amino acid signal peptide) was successfully expressed and secreted by MDA-MB435 cells.
  • CED1-4 significantly inhibited MDA-MB435 cell proliferation both in vitro and in vivo.
  • CED1-4 induced a significant increase in apoptosis, with a 22-fold rise in early apoptotic cells and a twofold increase in caspase 3 activity.
  • Down-regulation of integrin beta1 and blockage of c-fos mRNA expression were observed in CED1-4 transfected cells.

Conclusions:

  • Soluble truncated cadherin CED1-4 functions as an apoptotic inducer and growth inhibitor in the MDA-MB435 breast carcinoma cell line.
  • The observed anti-cancer effects of CED1-4 are potentially mediated by the down-regulation of integrin beta1 and the blockage of c-fos expression.

Related Concept Videos

Cadherins in Tissue Organization01:19

Cadherins in Tissue Organization

The cadherins are a superfamily of cell adhesion molecules comprising over 180 variants, with specific tissues expressing a particular combination of cadherin types. Cadherins generally exhibit homophilic binding; i.e., cadherins on one cell bind to cadherins of the same or closely related type on another cell. Thus, cells of the same type have a specific affinity to bind to each other and sort themselves into clusters to form tissues.
Cell Sorting During Development
Cell sorting plays an...
Structure of Cadherins01:25

Structure of Cadherins

The cadherins were one of the first cell adhesion molecules discovered; the term “cadherins”   is based on their calcium-dependent adhering properties. The first cadherins discovered on the epithelial, neuronal, and placental cells were named E-cadherin, P-cadherin, and N-cadherin, respectively. These classical cadherins share sequence and structural similarities. Other cadherins, including those involved in cell signaling, are grouped into non-classical cadherins. This diversity of cadherins...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Inhibition of CDK Activity02:34

Inhibition of CDK Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR activation may...
Cancer-Critical Genes II: Tumor Suppressor Genes01:05

Cancer-Critical Genes II: Tumor Suppressor Genes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...