Modulation of urokinase-type plasminogen activator and metalloproteinase activities in cultured mouse mammary-carcinoma cells: Enhancement by paclitaxel and inhibition by nocodazole

Paclitaxel is a potent anti-tumor drug used in the treatment of breast canc er. It induces de-centralization of the microtubular system in tumor cells, blocking cell division. In the search for dissemination to a secondary sit e, cancer cells are capable of degrading most components of the extracellul ar matrix via an extracellular proteolytic cascade, including urokinase-typ e plasminogen activator (uPA) and the matrix metalloproteinases (MMPs), In the present study, the effects of paclitaxel and nocodazole, 2 drugs known to affect microtubules with opposite mechanisms of action, have been tested for their effect on the secretion of uPA and MMPs in cultures of F311 mous e mammary-tumor cells. Tumor-derived uPA activity significantly increased a fter pre-treatment of tumor cells for 24 hr with micromolar concentrations of paclitaxel (4 mu M), while decreasing after pre-treatment with nocodazol e(1 mu M), A similar modulation was found for MMP-9 by zymographic analysis . Immunofluorescence and Western-blot analysis confirmed the formation of p arallel microtubule fragments in paclitaxel-treated cells and almost comple te de-polymerization of microtubules in nocodazole-treated ones, Our data s uggest that, through opposite actions on microtubule organization and dynam ics, paclitaxel and nocodazole exert inverse modulation of tumor-derived pr oteolytic activity in mammary tumor cells, (C) 1999 Wiley-Liss. Inc.