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Plasminogen Activator and Inhibitor Activity in Human Glioma Cells and Modulation by Sodium Butyrate¹

Cancer Chemotherapy Program, Pharmaceuticals and Biotechnology, Research and Development Division, Medical Products Department, E. I. Du Pont de Nemours & Co., Inc., Wilmington, Delaware 19898 [J. L. G., D. L. B., D. L. D.]; Department of Cell Biology, New York University Medical Center, 550 First Avenue, New York, New York 10016 [D. E. M.]; and Department of Neurological Surgery, Albert Einstein and Montefiore Medical Center, New York, New York 10467 [P. L. K.]

The activity of the serine protease plasminogen activator (PA), which correlates with tumorigenicity and metastatic capacity, was examined using the ¹²⁵I-labeled fibrin plate assay in cell extracts from four human glioma lines as a function of growth in vitro. Cell-associated inhibitory activity to plasmin and urokinase-type PA was also measured concurrently. The relative PA activities differed markedly among the lines, whereas inhibitory activities did not. Two lines, SNB-19 and SNB-75, exhibited maximal PA activities (1–6 m Plough units/µg protein) as cultures approached confluence, whereas two other lines, SNB-56 and SNB-78, expressed low PA activity at all times (<0.2 m Plough units/µg protein). The PA of SNB-19 cell extracts was predominantly urokinase-type PA. In addition to having the highest PA levels, SNB-19 and SNB-75 were the most clonogenic in soft agar and tumorigenic in nude mice. In contrast, SNB-56 and SNB-78 were poorly clonogenic in soft agar and were not tumorigenic in nude mice. Measured directly, inhibitory activities to plasmin, urokinase-type PA, and tissue-type PA were detected in SNB-19 (high PA) and SNB-56 (low PA) cell extracts. However, there were no qualitative or quantitative differences in inhibitor effects between SNB-19 and SNB-56 suggesting that the differences in PA activity between these lines resulted from changes in PA activity and were not due to differential plasminogen activator inhibitor effects. The ability of the differentiating agent sodium butyrate (NaB) to modulate total PA activity was also examined. Peak SNB-19 cell PA activity was decreased in a concentration (K_i, 0.75 mM) and time-dependent manner by the addition of nontoxic amounts of NaB. The dose-dependent decrease in PA activity induced by NaB was most likely due to an effect on PA itself, since the action of inhibitor on urokinase was unchanged in response to NaB. These results suggest that net cellular PA activity in glioma cells is a balance between relative PA activity and inhibitor(s) effects and that this balance can be modulated by sodium butyrate.

¹ Supported in part by a grant to D. B. Rifkin from the NIH (CA23753).

² To whom correspondence and reprint requests should be sent, at E. I. Du Pont de Nemours & Co., Inc., Glenolden Laboratory, 500 S. Ridgeway Avenue, Glenolden, PA 19036.

³ Present address: Schering Corporation, Bloomfield, NJ 07003.

Received 3/13/87. Revised 10/ 1/87. Accepted 10/15/87.

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