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Lysosomotropic drugs inhibit maturation of transforming growth factor-

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Abstract:

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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  • Published since 1929, this monthly journal reports current research in all aspects of physiology, nutrition, pharmacology, and toxicology, contributed by recognized experts and scientists. It publishes symposium reviews and award lectures and occasionally dedicates entire issues or portions of issues to subjects of special interest to its international readership.
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