Alpha1-antitrypsin and its multiply effects on breast carcinoma MDA-MB 468 cell growth and invasiveness

I. Zelvyte, M.D., S. Janciauskiene

Department of Medicine, University of Lund, Malmo, Sweden

Background: Tumor invasion and metastasis involve proteolytic activities of malignant cells to detach from extracellular matrices. The degradation of extracellular matrix during cancer invasion results from action of several proteolytic enzyme systems, including serine protease inhibitor system. Alpha1-antitrypsin (AAT) is a serine proteinase inhibitor, its plasma concentration can rise by 5-fold during inflammation, infection and malignant diseases. AAT is found not only in native, inhibitory active form, but also in several other, non-inhibitory forms including cleaved and /or degraded forms. Aim: To test a hypothesis that AAT dependent on its molecular form may have multiple effects on tumor cell activity. Methods: Human breast cancer cells, MDA-MB 468, were cultured alone and stimulated with native AAT or C-terminal fragment of AAT (C-36) (5µM) for 2, 24 and 48 h. We analysed cell proliferation (H 3-thymidine incorporation assay), invasiveness (cell invasion assay), levels of transforming growth factor beta-1(TGFα) (ELISA method), expression of transcription factor-NFêB (electrophoretic shift assay) and metalloproteinase activity (10% zymogram electrophoresis). Results: The cells exposed to native AAT decrease proliferation up to 75% (p<0.01) and TGFα levels up to 51% (p<0.05) while cells treated with C-36 increase proliferation and TGFα levels up to 200% (p<0,01) and 65% (p<0.05), respectively. C-36 also increases cell invasiveness by 40% (p<0.01), metalloproteinase activity and NFêB expression compared with non-stimulated cells or treated with AAT. Conclusions: For the first time we show that the same protein such as AAT dependent on its molecular form can play various biological roles on tumor cell growth and spread.

KEY WORDS: Proteinases, alpha1-antitrypsin, tumor cells, proliferation, invasiveness.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Metastasis.