title: Lysosomotropic drugs inhibit maturation of transforming growth factor-beta.
abstract: Transforming growth factor-beta (TGFbeta) is synthesized as a precursor protein, pro-TGFbeta, 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-TGFbeta processing and decrease TGFbeta 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-TGFbeta processing, thereby significantly reducing the levels of secreted TGFbeta. Brefeldin A, bafilomycin A1, ammonium chloride, and monensin also prevented pro-TGFbeta processing. The alkalinizing lysosomotropic drugs chloroquine, hydroxychloroquine, amodiaquine, and azithromycin had a similar effect on the overall production of mature bioactive TGFbeta. Reduced levels of secreted TGFbeta were also associated with a decrease in Smad2 signaling. Mice treated with chloroquine showed a decrease in bronchoalveolar lavage fluid TGFbeta. We conclude that alkalinizing lysosomotropic drugs inhibit pro-TGFbeta processing.
authors.affiliation: Pulmonary Research Unit, Faculty of Medicine and Health Sciences, Universite de Sherbrooke, Sherbrooke, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Basque
authors.forename: Marc
authors.initials: M
authors.lastname: Martel
authors.forename: Richard
authors.initials: R
authors.lastname: Leduc
authors.forename: André M
authors.initials: AM
authors.lastname: Cantin