Lysosomotropic drugs inhibit maturation of transforming growth factor-beta

Can J Physiol Pharmacol. 2008 Sep;86(9):606-12. doi: 10.1139/y08-063.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amodiaquine / pharmacology
  • Animals
  • Azithromycin / pharmacology
  • Blotting, Western
  • Bronchoalveolar Lavage Fluid / cytology
  • Cell Line
  • Cell Line, Tumor
  • Chloroquine / pharmacology
  • Enzyme-Linked Immunosorbent Assay
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Furin / metabolism
  • Humans
  • Hydroxychloroquine / pharmacology
  • Kinetics
  • Lysosomes / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Stem Cells / drug effects
  • Stem Cells / metabolism
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / biosynthesis*


  • Transforming Growth Factor beta
  • Amodiaquine
  • Hydroxychloroquine
  • Azithromycin
  • Chloroquine
  • Furin