Polysialylated NCAM represses E-cadherin-mediated cell-cell adhesion in pancreatic tumor cells
Susanne C Schreiber1, Klaudia Giehl, Caroline Kastilan
1Institute of Zoology 2, University Karlsruhe, Karlsruhe, Germany.
Background & Aims:
Inhibition of cell-cell adhesion between epithelial cells represents an early step during tumor metastasis. Down-regulation or perturbation of E-cadherin-mediated adherens junctions is an essential requirement in this process.
Methods:
The interaction between polysialylated neural cell adhesion molecule (PSA-NCAM) and the E-cadherin adhesion complex was studied by coimmunoprecipitation assays. The presence of PSA-NCAM was correlated with tumor invasion by using cell-cell aggregation and cell migration assays. The importance of polysialic acid (PSA) in the interaction of NCAM with E-cadherin and inhibition of cell-cell adhesion was confirmed by enzymatic removal of PSA from NCAM and down-regulation of PSA-transferases by siRNA.
Results:
Expression of oncogenic K-Ras(V12) in pancreatic carcinoma cells resulted in induction of PSA-NCAM expression and reduced E-cadherin-mediated cellular adhesion. The association of PSA-NCAM with the E-cadherin adhesion complex correlated with decreased cell-cell aggregation and elevated cell migration of pancreatic carcinoma cells. Enzymatic removal of PSA from NCAM or reduction of polysialyltransferase expression led to reduced association between NCAM and E-cadherin and subsequently increased E-cadherin-mediated cell-cell aggregation and reduced cell migration.
Conclusions:
Our data suggest the induction of PSA-NCAM by oncogenic K-Ras as a novel molecular mechanism by which E-cadherin-mediated cellular adhesion is reduced and dissemination of tumor cells is facilitated.
Insights
Oncogenic K-Ras induces polysialylated neural cell adhesion molecule (PSA-NCAM), which disrupts E-cadherin adhesion. This promotes pancreatic tumor cell migration and metastasis.
Area of Science:
- Cell Biology
- Cancer Research
- Molecular Oncology
Background:
- Tumor metastasis involves reduced epithelial cell-cell adhesion.
- E-cadherin-mediated adherens junctions are crucial for cell adhesion.
- Perturbation of E-cadherin is essential for tumor cell dissemination.
Purpose of the Study:
- To investigate the interaction between PSA-NCAM and E-cadherin.
- To determine the role of PSA-NCAM in pancreatic tumor cell invasion.
- To elucidate the mechanism by which K-Ras influences cell adhesion.
Main Methods:
- Coimmunoprecipitation assays to study protein interactions.
- Cell-cell aggregation and migration assays to assess invasion.
- Enzymatic removal of PSA and siRNA to down-regulate PSA-transferases.
Main Results:
- Oncogenic K-Ras induced PSA-NCAM expression in pancreatic cells, reducing E-cadherin adhesion.
- PSA-NCAM association with E-cadherin correlated with decreased aggregation and increased migration.
- PSA removal or reduced PSA-transferase expression restored cell adhesion and reduced migration.
Conclusions:
- Oncogenic K-Ras induces PSA-NCAM, a novel mechanism reducing E-cadherin adhesion.
- This process facilitates pancreatic tumor cell dissemination.
- Targeting PSA-NCAM may offer therapeutic strategies for metastasis.
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