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Lysosomotropic drugs inhibit maturation of transforming growth factor-

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Transforming growth factor- (TGF) is synthesized as a precursor protein, pro-TGF, 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-TGF processing and decrease TGF 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-TGF processing, thereby significantly reducing the levels of secreted TGF. Brefeldin A, bafilomycin A1, ammonium chloride, and monensin also prevented pro-TGF processing. The alkalinizing lysosomotropic drugs chloroquine, hydroxychloroquine, amodiaquine, and azithromycin had a similar effect on the overall production of mature bioactive TGF. Reduced levels of secreted TGF were also associated with a decrease in Smad2 signaling. Mice treated with chloroquine showed a decrease in bronchoalveolar lavage fluid TGF. We conclude that alkalinizing lysosomotropic drugs inhibit pro-TGF processing.

Le facteur de croissance transformant  (TGF) est synthétisé en tant que protéine en amont : le pro-TGF qui doit être scindé par une protéinase analogue à la furine avant de devenir biologiquement actif. Nous posons donc l’hypothèse selon laquelle l’alcalinisation de l’ensemble réseau trans-golgien/endosome stoppe la production de pro-TGF et diminue la sécrétion de TGF. Nous avons testé cette hypothèse dans une cellule épithéliale d’une alvéole A549, dans une lignée cellulaire de glioblastome T98G et chez des souris C57BL/6. L’inhibition de l’activité analogue à celle de la furine par la chlorométhylcétone de decanoyl-RVKR arrête la production de pro-TGF et cause une diminution significative de la concentration de TGF sécrétée. La bréfeldine A, la bafilomycine A1, le chlorure d’ammonium et la monensine arrêtent aussi la production de pro-TGF. La chloroquine, l’hydroxychloroquine, l’amodiaquine et l’azithromycine ont aussi un effet similaire sur la production globale de TGF bioactif arrivé à terme. La diminution de la sécrétion de TGF est aussi associée au fléchissement de la signalisation de Smad-2. Les souris traitées à la chloroquine révèlent une diminution de la concentration de TGF dans le liquide de lavage bronchoalvéolaire. En conclusion, les drogues lysosomotropiques au pouvoir alcalinisant arrêtent la production de pro-TGF.

Document Type: Research Article

Publication date: September 1, 2008

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