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5-Fluorouracil Blocks Transforming Growth Factor-–Induced ₂ Type I Collagen Gene (COL1A2) Expression in Human Fibroblasts via c-Jun NH₂-Terminal Kinase/Activator Protein-1 Activation

Institut National de la Santé et de la Recherche Médicale U532, Skin Research Institute, Saint-Louis Hospital, Paris, France

5-Fluorouracil (5-FU), a pyrimidine analog widely used in cancer chemotherapy and in glaucoma surgery, has recently shown some efficacy in the treatment of keloids, scars that overgrow the boundaries of original wounds. Given the physiopathological importance of transforming growth factor- (TGF-) in keloid and scar formation, we have examined whether the clinical benefits from 5-FU treatment may result from its capacity to interfere with TGF- signaling and resulting activation of type I collagen gene expression. Using various molecular approaches to study the mechanisms underlying 5-FU effects, we have demonstrated that 5-FU antagonizes TGF-–driven COL1A2 transcription and associated type I collagen production by dermal fibroblasts. In addition, 5-FU inhibits both SMAD3/4-specific transcription and formation of SMAD/DNA complexes induced by TGF-. 5-FU induces c-Jun phosphorylation and activates both AP-1-specific transcription and DNA binding. Overexpression of an antisense c-jun expression vector, or that of a dominant-negative form of MKK4 that interferes with c-Jun N-terminal kinase (JNK) activation, blocks the inhibitory activity of 5-FU on TGF-–induced COL1A2 transcription. Furthermore, in a cellular context devoid of JNK activity (i.e., JNK^–/– fibroblasts), 5-FU inhibits neither formation of SMAD/DNA complexes nor SMAD-driven COL1A2 transcription in response to TGF-. Together, these results identify 5-FU as a potent inhibitor of TGF-/SMAD signaling, capable of blocking TGF-–induced, SMAD-driven up-regulation of COL1A2 gene expression in a JNK-dependent manner. We thus provide a molecular explanation to the observed clinical benefits of 5-FU in the treatment of keloids and hypertrophic scars.

Address correspondence to: Dr. Franck Verrecchia, INSERM U532, Institut de Recherche sur la Peau, Pavillon Bazin, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75475 Paris cedex 10, France. E-mail: verrecchia{at}chustlouis.fr

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