High
biological activity of the
transforming growth factor (
TGF)-beta-Smad pathway characterizes the malignant phenotype of
malignant gliomas and confers poor prognosis to
glioma patients. Accordingly,
TGF-beta has become a novel target for the experimental treatment of these
tumors.
TGF-beta is processed by
furin-like
proteases (FLP) and secreted from cells in a latent complex with its processed propeptide, the latency-associated
peptide (LAP).
Latent TGF-beta-binding protein 1 (LTBP-1) covalently binds to this small latent
TGF-beta complex (SLC) and regulates its function, presumably via interaction with the extracellular matrix (ECM). We report here that the levels of LTBP-1
protein in vivo increase with the grade of
malignancy in
gliomas. LTBP-1 is associated with the ECM as well as secreted into the medium in cultured
malignant glioma cells. The release of LTBP-1 into the medium is decreased by the inhibition of FLP activity. Gene-transfer mediated overexpression of LTBP-1 in
glioma cell lines results in an increase inTGF-beta activity. Accordingly, Smad2 phosphorylation as an intracellular marker of
TGF-beta activity is enhanced. Conversely, LTBP-1 gene silencing reduces
TGF-beta activity and Smad2 phosphorylation without affecting
TGF-beta protein levels. Collectively, we identify LTBP-1 as an important modulator of
TGF-beta activation in
glioma cells, which may contribute to the malignant phenotype of these
tumors.