The degradation of extracellular matrix during cancer invasion results from the action of several protease and protease inhibitor systems. Alpha(1)-Antitrypsin (AAT) is a serine proteinase inhibitor produced by various tumour cells, and its plasma concentration rises during inflammation, infection and malignant diseases. AAT is found in a native, inhibitory active form, but also in other, non-inhibitory forms including cleaved and/or degraded. To test a hypothesis that AAT dependent on its molecular form may have multiple effects on tumour cell behaviour, breast cancer cells, MDA-MB 468, were cultured alone or stimulated with a native AAT or its C-terminal fragment (C-36) at a concentration of 5 micromol/l for 2, 24 and 48 hours. Native AAT added to the cells for 2 hours enhanced transforming growth factor beta 1 (TGFbeta1) levels by 50%, but inhibited cell proliferation (by 61%), reduced interleukin 6 (IL-6) levels (by 87%) and activity (by about 66%), compared with non-stimulated cells. Native AAT showed similar, but less pronounced, effects when added to the cells for 24 and 48 hours. Under the same experimental conditions the cells exposed to the C-36 peptide significantly increased in proliferation, invasiveness and showed higher IL-6 levels. In addition, cells treated with the C-36 for 48 hours increased in NFkappaB (nuclear factor kappa B) activity. These results indicate that AAT, dependent on its molecular form, can both suppress and induce breast tumour cell biological activity in vitro.
Background: Tumor microenvironment, which is largely affected by inflammatory cells, is a crucial participant in the neoplastic process through promotion of cell proliferation, survival and migration. We measured the effects of polymorphonuclear neutrophil (PMN) conditioned medium alone, and supplemented with serine proteinase inhibitor α-1 antitrypsin (AAT) or its C-terminal fragment (C-36 peptide), on cultured lung cancer cells.
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