Urokinase receptor in human malignant mesothelioma cells: role in
tumor cell mitogenesis and proteolysis.
D, Sreerama Shetty Ph, Anuradha Kumar Ph. D., Alice Johnson, Ph. D,
Siegfried Pueblitz, M. D. and Steven Idell, M. D., Ph. D.
Departments of Medicine, Biochemistry and Pathology, The University
of Texas Health Science Center at Tyler
APStracts 2:0011L, 1995.
Urokinase (uPA) interacts with its receptor (uPAR) to promote
proteolysis and tumor migration, functions of potential importance in
the pathogenesis of malignant mesothelioma. Immunohistochemistry of
human malignant mesothelioma tissue and mesothelioma cells (MS-1)
showed that mesothelioma cells express uPAR. We isolated uPAR from
MS-1 cells by metabolic labeling and showed that it could be induced
by phorbol myristate acetate (PMA), lipopolysaccharide (LPS),
transforming growth factor-beta (TGF-b) or tumor necrosis factor
-alpha (TNF-a). Experiments with MS-1 cells showed that uPA binding
was saturable, specific and reversible with a mean Kd of 5.4 +/- 1.1
nM. Binding was inhibited by a blocking antibody to uPAR and by the
uPA amino-terminal fragment (ATF), but not by low molecular uPA. uPAR
expression was regulated transcriptionally and translationally;
antisense oligonucleotides blocked expression of uPAR protein.
Plasminogen activator inhibitor-1 (PAI-1) inhibited PA activity of
preformed uPA/uPAR complexes and increased cycling of the receptor
from the cell surface. Stimulation of subconfluent MS-1 cells by high
molecular weight or recombinant uPA, but not ATF or low molecular
weight frament, caused concentration-dependent incorporation of 3H
-thymidine. These data indicate a novel mechanism by which malignant
mesothelioma cells localize pericellular proteolysis and concurrently
regulate tumor cell proliferation.
Received 8 August 1994; accepted in final form 16 January 1995.
APS Manuscript Number L227-4.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 24 February 1995.