Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Enhanced matrix metalloproteinase expression in cancer cells by the cleaved form of alpha-1-antitrypsin

S Janciauskiene PhD

Dept Medicine, University Hospital Malmö, Malmö, Sweden,

AIMS. Previous studies revealed that various tumor cells produce alpha-1-antitrypsin (AAT) and that AAT –positive adenocarcinomas of colon and lung had a worse prognosis than AAT-negative ones. A major function of AAT is the inhibition of over expressed serine proteinases during inflammation. It is also known that AAT is a good substrate for matrix metalloproteinases (MMPs), which degrade AAT. On the other hand, MMPs have an important role in tumor progression, particularly in metastatic events via their degrading activity against various extracellular matrix proteins. To test for a possible link between the tumor cell-generated AAT and MMPs, we studied the effects of the C-terminal fragment of AAT on tumor cell activation in vitro. METHODS. Cultured cells derived from tumor cells of human origin (lung cancer H2981, melanoma H1477 and H1462). Cells were cultured alone or in the presents of native AAT (2mg/mL), cleaved fragment of AAT (10 mikromol/L) or endotoxin (1g/L) for various time intervals up to 48 hours. After incubation, the medium was collected and analyzed by 10% SDS-PAGE followed by Western blot (to determine molecular forms of AAT) and by ELISA method (to determine levels of gelatinase B, MMP-9). RESULTS. We found that all tested cancer cells alone produce significant amounts of native and various cleaved forms of AAT, and that the native AAT added to the cell cultures becomes largely degraded. Cleaved fragment of AAT added to cancer cell cultures for 30 min induced production of gelatinase B (MMP-9) by about 2,5-fold compared to controls. CONCLUSIONS. These results indicate that the cleaved form of AAT which could be generated by MMPs, may stimulate cancer cells to produce more MMPs and play a critical role in early-stage of tumor progression. This also suggests that changes in structure occurring upon AAT cleavage could alter its functional properties with potential pathological consequences.

KEY WORDS: serpins, inflammation.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on prognostic markers.