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

• Published in: International journal of cancer Vol. 83; no. 2; pp. 242 - 246
• Main Authors: Alonso, Daniel F., Farina, Hernán G., Arregui, Carlos, Aon, Miguel A., Gomez, Daniel E.
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 08-10-1999; Wiley-Liss
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents, Phytogenic - pharmacology; Biological and medical sciences; Collagenases - metabolism; General aspects; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - enzymology; Mammary Neoplasms, Experimental - pathology; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Medical sciences; Metalloendopeptidases - antagonists & inhibitors; Metalloendopeptidases - metabolism; Mice; Mice, Inbred BALB C; Microtubules - drug effects; Nocodazole - pharmacology; Paclitaxel - pharmacology; Pharmacology. Drug treatments; Secretory Rate - drug effects; Tubulin - metabolism; Tumor Cells, Cultured; Urokinase-Type Plasminogen Activator - antagonists & inhibitors; Urokinase-Type Plasminogen Activator - metabolism; Antineoplastic agent; u-Plasminogen activator; Carcinoma; Cytotoxicity; Metalloendopeptidases; Nocodazole; Thiophene derivatives; Regulation(control); Enzymatic activity; Taxane derivatives; Established cell line; Paclitaxel; Mammary gland; Mechanism of action; Antimitotic; Serine endopeptidases; Enzyme; Rodentia; Malignant tumor; In vitro; Mammary gland diseases; Peptidases; Vertebrata; Mammalia; Mouse; Animal; Hydrolases
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/(SICI)1097-0215(19991008)83:2<242::AID-IJC16>3.0.CO;2-8

Paclitaxel is a potent anti‐tumor drug used in the treatment of breast cancer. It induces de‐centralization of the microtubular system in tumor cells, blocking cell division. In the search for dissemination to a secondary site, cancer cells are capable of degrading most components of the extracellular matrix via an extracellular proteolytic cascade, including urokinase‐type 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 F3II mouse mammary‐tumor cells. Tumor‐derived uPA activity significantly increased after pre‐treatment of tumor cells for 24 hr with micromolar concentrations of paclitaxel (4 μM), while decreasing after pre‐treatment with nocodazole (1 μM). A similar modulation was found for MMP‐9 by zymographic analysis. Immunofluorescence and Western‐blot analysis confirmed the formation of parallel microtubule fragments in paclitaxel‐treated cells and almost complete de‐polymerization of microtubules in nocodazole‐treated ones. Our data suggest that, through opposite actions on microtubule organization and dynamics, paclitaxel and nocodazole exert inverse modulation of tumor‐derived proteolytic activity in mammary tumor cells. Int. J. Cancer 83:242–246, 1999. © 1999 Wiley‐Liss, Inc.