Lysosomotropic drugs inhibit maturation of transforming growth factor-β
- 1 September 2008
- journal article
- Published by Canadian Science Publishing in Canadian Journal of Physiology and Pharmacology
- Vol. 86 (9), 606-612
- https://doi.org/10.1139/y08-063
Abstract
Transforming growth factor-β (TGFβ) is synthesized as a precursor protein, pro-TGFβ, that must be cleaved by a furin-like proteinase before it becomes biologically active. We hypothesized that alkalinization of the trans-Golgi network (TGN)/endosome system may suppress pro-TGFβ processing and decrease TGFβ secretion. This hypothesis was tested in human A549 alveolar epithelial and T98G glioblastoma cell lines and in C57BL/6 mice. Inhibition of furin-like activity with decanoyl-RVKR chloromethylketone suppressed pro-TGFβ processing, thereby significantly reducing the levels of secreted TGFβ. Brefeldin A, bafilomycin A1, ammonium chloride, and monensin also prevented pro-TGFβ processing. The alkalinizing lysosomotropic drugs chloroquine, hydroxychloroquine, amodiaquine, and azithromycin had a similar effect on the overall production of mature bioactive TGFβ. Reduced levels of secreted TGFβ were also associated with a decrease in Smad2 signaling. Mice treated with chloroquine showed a decrease in bronchoalveolar lavage fluid TGFβ. We conclude that alkalinizing lysosomotropic drugs inhibit pro-TGFβ processing.Keywords
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