Caspase‐3 enhances lung metastasis and cell migration in a protease‐independent mechanism through the ERK pathway
| Autor: | Chien Hsin Lee, Chung Chen Su, Jyun Yuan Huang, Wen Tsan Chang, Yu Ping Lin, Bei Chang Yang, Yu Jung Cheng |
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| Rok vydání: | 2008 |
| Předmět: |
MAPK/ERK pathway
Cancer Research Lung Neoplasms Blotting Western Gene Expression Mice Nude Apoptosis Caspase 3 Biology Ceramides Cell Line Mice Cell Movement medicine Animals Humans Neoplasm Invasiveness Neoplasm Metastasis Phosphorylation RNA Small Interfering Extracellular Signal-Regulated MAP Kinases Ceramide synthase A549 cell Microscopy Confocal Cell migration Flow Cytometry Immunohistochemistry Xenograft Model Antitumor Assays Cysteine protease Sphingomyelin Phosphodiesterase Oncology Mitogen-activated protein kinase Cancer research biology.protein Acid sphingomyelinase Peptide Hydrolases medicine.drug |
| Zdroj: | International Journal of Cancer. 123:1278-1285 |
| ISSN: | 1097-0215 0020-7136 |
| DOI: | 10.1002/ijc.23592 |
| Popis: | Caspase-3 is known as a cysteine protease that primarily executes the cell death program. However, some tumors express higher levels of caspase-3 in positive correlation with malignancy. Here, we showed that caspase-3 can promote tumor metastasis in a protease-independent mechanism. Ectopic expression of caspase-3 enhanced lung metastasis and cell motility of caspase-3 deficient MCF-7 cells. By contrast, caspase-3 siRNA reduced the invasiveness and metastasis ability of A549 cells that express high level of caspase-3. Moreover, caspase-3 induced ERK activation. Alteration of caspase-3 by introducing non-processable mutation at its cleavage site or treatment of caspase-3 inhibitor did not diminish the caspase-3-associated increases in ERK phosphorylation and cell migration. Confocal microscopy study showed that caspase-3 was not physically associated with ERK. Inhibiting ceramide formation by blockage of the ceramide synthase or acid sphingomyelinase activity resulted in significant reduction of ERK phosphorylation and cell migration. In summary, caspase-3 induces ERK activation through a ceramide-dependant, protease activity-independent mechanism, which represents a novel role of caspase-3 in tumor metastasis. |
| Databáze: | OpenAIRE |
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