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Polyamine-dependent expression of the matrix metalloproteinase matrilysin in a human colon cancer-derived cell line
U M Wallon1, L R Shassetz, A E Cress
1Department of Radiation Oncology, University of Arizona Health Sciences Center, Tucson 85724.
Abstract:
Matrilysin, which is a member of the matrix metalloproteinase family and is implicated in colon cancer invasion, is expressed in human colon adenocarcinoma-derived SW1116 cells. We investigated the effect of alpha-difluoromethylornithine (DFMO) on matrilysin expression in this cell line because others have shown that DFMO can inhibit invasion and carcinogenesis in epithelial tissues, including the colon, in experimental models. DFMO reduced extracellular levels of matrilysin protein after 4 d of treatment. Intracellular levels of matrilysin protein were minimally affected by DFMO treatment. The decrease in extracellular matrilysin protein levels caused by DFMO was not a consequence of lowered steady-state levels of matrilysin mRNA. After 4 d of exposure, the amount of this transcript was higher in DFMO-treated cells than in untreated cultures, whereas the mRNA stabilities were similar. These data show that polyamine depletion by DFMO can suppress the expression of matrilysin, a gene product thought to be involved in tumor invasion. The decrease in extracellular matrilysin protein caused by DFMO treatment appears to be due to a posttranscriptional mechanism, although transcription of this gene also seems to be affected by polyamines in SW1116 cells.
Insights
Alpha-difluoromethylornithine (DFMO) reduces extracellular matrilysin protein, a key factor in colon cancer invasion. This effect occurs post-transcriptionally, suggesting DFMO
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Matrilysin, a matrix metalloproteinase, is involved in colon cancer invasion.
- Alpha-difluoromethylornithine (DFMO) shows potential in inhibiting epithelial carcinogenesis.
Purpose of the Study:
- To investigate the effect of DFMO on matrilysin expression in SW1116 colon adenocarcinoma cells.
- To elucidate the mechanism by which DFMO influences matrilysin expression.
Main Methods:
- Treatment of SW1116 cells with DFMO for 4 days.
- Quantification of extracellular and intracellular matrilysin protein levels.
- Analysis of matrilysin mRNA levels and stability.
Main Results:
- DFMO significantly reduced extracellular matrilysin protein levels.
- Intracellular matrilysin protein levels were minimally affected by DFMO.
- DFMO treatment increased matrilysin mRNA levels, indicating a post-transcriptional regulation mechanism.
Conclusions:
- Polyamines depletion by DFMO suppresses extracellular matrilysin expression in colon cancer cells.
- The reduction in extracellular matrilysin is primarily mediated by a post-transcriptional mechanism.
- DFMO may represent a therapeutic strategy for colon cancer by targeting matrilysin.