1. Fibroblast-specific inhibition of TGF-β1 signaling attenuates lung and tumor fibrosis
- Author
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Wei, Ying, Kim, Thomas J, Peng, David H, Duan, Dana, Gibbons, Don L, Yamauchi, Mitsuo, Jackson, Julia R, Le Saux, Claude J, Calhoun, Cheresa, Peters, Jay, Derynck, Rik, Backes, Bradley J, and Chapman, Harold A
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Lung ,Cancer ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Aetiology ,Development of treatments and therapeutic interventions ,A549 Cells ,Amino Acid Oxidoreductases ,Animals ,Drug Screening Assays ,Antitumor ,Enzyme Inhibitors ,Epithelial-Mesenchymal Transition ,Fibroblasts ,Humans ,Lung Neoplasms ,Mice ,Neoplasm Metastasis ,Neoplasm Proteins ,Phenols ,Protein Kinase Inhibitors ,Protein Serine-Threonine Kinases ,Pulmonary Fibrosis ,Receptor ,Transforming Growth Factor-beta Type I ,Receptors ,Transforming Growth Factor beta ,Signal Transduction ,Transforming Growth Factor beta1 ,Medical and Health Sciences ,Immunology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
TGF-β1 signaling is a critical driver of collagen accumulation and fibrotic disease but also a vital suppressor of inflammation and epithelial cell proliferation. The nature of this multifunctional cytokine has limited the development of global TGF-β1 signaling inhibitors as therapeutic agents. We conducted phenotypic screens for small molecules that inhibit TGF-β1-induced epithelial-mesenchymal transition without immediate TGF-β1 receptor (TβR) kinase inhibition. We identified trihydroxyphenolic compounds as potent blockers of TGF-β1 responses (IC50 ~50 nM), Snail1 expression, and collagen deposition in vivo in models of pulmonary fibrosis and collagen-dependent lung cancer metastasis. Remarkably, the functional effects of trihydroxyphenolics required the presence of active lysyl oxidase-like 2 (LOXL2), thereby limiting effects to fibroblasts or cancer cells, the major LOXL2 producers. Mechanistic studies revealed that trihydroxyphenolics induce auto-oxidation of a LOXL2/3-specific lysine (K731) in a time-dependent reaction that irreversibly inhibits LOXL2 and converts the trihydrophenolic to a previously undescribed metabolite that directly inhibits TβRI kinase. Combined inhibition of LOXL2 and TβRI activities by trihydrophenolics resulted in potent blockade of pathological collagen accumulation in vivo without the toxicities associated with global inhibitors. These findings elucidate a therapeutic approach to attenuate fibrosis and the disease-promoting effects of tissue stiffness by specifically targeting TβRI kinase in LOXL2-expressing cells.
- Published
- 2017