Chondroitin sulfate–mediated N-cadherin/β-catenin signaling is associated with basal-like breast cancer cell invasion
| Autor: | Hiroshi Kitagawa, Satomi Nadanaka, Hiroki Kinouchi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Glycobiology and Extracellular Matrices Breast Neoplasms MMP9 Endocytosis Biochemistry Extracellular matrix 03 medical and health sciences chemistry.chemical_compound Cell Movement Cell Line Tumor Extracellular Chondroitin Humans Molecular Biology beta Catenin Glycosaminoglycans Cadherin Chondroitin Sulfates Cell Biology Cadherins Cell biology Extracellular Matrix 030104 developmental biology chemistry Matrix Metalloproteinase 9 Cancer cell Female Sulfotransferases Intracellular Signal Transduction |
| Popis: | Tumor metastasis involves cancer cell invasion across basement membranes and interstitial tissues. The initial invasion step consists of adherence of the tumor cell to the extracellular matrix (ECM), and this binding transduces a variety of signals from the ECM to the tumor cell. Accordingly, it is critical to establish the mechanisms by which extracellular cues influence the intracellular activities that regulate tumor cell invasion. Here, we found that invasion of the basal-like breast cancer cell line BT-549 is enhanced by the ECM component chondroitin sulfates (CSs). CSs interacted with and induced proteolytic cleavage of N-cadherin in the BT-549 cells, yielding a C-terminal intracellular N-cadherin fragment that formed a complex with β-catenin. Of note, the cleavage of N-cadherin increased cytoplasmic and nuclear β-catenin levels; induced the matrix metalloproteinase 9 (MMP9) gene, a target of β-catenin nuclear signaling; and augmented the invasion potential of the cells. We also found that CS-induced N-cadherin proteolysis requires caveolae-mediated endocytosis. An inhibitor of that process, nystatin, blocked both the endocytosis and proteolytic cleavage of N-cadherin induced by CS and also suppressed BT-549 cell invasion. Knock-out of chondroitin 4-O-sulfotransferase-1 (C4ST-1), a key CS biosynthetic enzyme, suppressed activation of the N-cadherin/β-catenin pathway through N-cadherin endocytosis and significantly decreased BT-549 cell invasion. These results suggest that CSs produced by C4ST-1 might be useful therapeutic targets in the management of basal-like breast cancers. |
| Databáze: | OpenAIRE |
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