Pirfenidone anti-fibrotic effects are partially mediated by the inhibition of MUC1 bioactivation.

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Ballester B, Milara J, Cortijo J

Pirfenidone anti-fibrotic effects are partially mediated by the inhibition of MUC1 bioactivation.

Oncotarget. 2020 Apr 14;11(15):1306-1320. doi: 10.18632/oncotarget.27526. eCollection 2020 Apr 14.

PubMed ID
32341751 [ View in PubMed
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Abstract

Pirfenidone is a pleiotropic molecule approved to treat idiopathic pulmonary fibrosis (IPF). Pirfenidone has demonstrated to downregulate transforming growth factor-beta1 (TGF-beta1) cellular effects. However, its anti-fibrotic mechanism remains unclear. Here, we aim to analyze the effects of pirfenidone on the TGF-beta1 canonical and non-canonical pathways, as well as, on the most characteristic IPF cellular processes. Results observed in this work showed that TGF-beta1-induced canonical SMAD3 and non-canonical ERK1/2 phosphorylations were not inhibited by pirfenidone in alveolar A549 and lung fibroblasts MRC5 cells. In contrast, pirfenidone inhibited TGF-beta1-induced MUC1-CT Thr(41) (1224) and Tyr(46) (1229) phosphorylations, thus reducing the beta-catenin activation. Additionally, immunoprecipitation and immunofluorescence studies in ATII cells and lung fibroblasts showed that pirfenidone inhibited the formation and nuclear translocation of the transcriptional fibrotic TGF-beta1-induced phospho-SMAD3/MUC1-CT/active-beta-catenin complex, and consequently the SMAD-binding element activation (SBE). This study provided also evidence of the inhibitory effect of pirfenidone on the TGF-beta1-induced ATII to mesenchymal and fibroblast to myofibroblast transitions, fibroblast proliferation and ATII and fibroblast senescence. Therefore, it indicates that pirfenidone's inhibitory effect on TGF-beta1-induced fibrotic cellular processes is mediated by the inhibition of MUC1-CT phosphorylation, beta-catenin activation, nuclear complex formation of phospho-SMAD3/MUC1-CT/active beta-catenin and SBE activation, which may be of value to further develop anti-fibrotic IPF therapies.

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