Hexokinase 2 couples glycolysis with the profibrotic actions of TGF-β
| Autor: | Mahefatiana Andrianifahanana, Mi-Yeon Jung, Edward B. Leof, Kyle J. Schaefbauer, Xueqian Yin, Danielle M. Hernandez, Jeong Han Kang, Malay Choudhury |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
medicine.medical_treatment
Biochemistry Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Transforming Growth Factor beta Fibrosis Hexokinase medicine Animals Molecular Biology Transcription factor 030304 developmental biology 0303 health sciences Gene knockdown Growth factor Lonidamine Cell migration 3T3 Cells Cell Biology medicine.disease Cell biology chemistry 030220 oncology & carcinogenesis Signal transduction Glycolysis Signal Transduction Transforming growth factor |
| Zdroj: | Science Signaling. 12 |
| ISSN: | 1937-9145 1945-0877 |
| Popis: | Metabolic dysregulation in fibroblasts is implicated in the profibrotic actions of transforming growth factor-β (TGF-β). Here, we present evidence that hexokinase 2 (HK2) is important for mediating the fibroproliferative activity of TGF-β both in vitro and in vivo. Both Smad-dependent and Smad-independent TGF-β signaling induced HK2 accumulation in murine and human lung fibroblasts through induction of the transcription factor c-Myc. Knockdown of HK2 or pharmacological inhibition of HK2 activity with Lonidamine decreased TGF-β-stimulated fibrogenic processes, including profibrotic gene expression, cell migration, colony formation, and activation of the transcription factors YAP and TAZ, with no apparent effect on cellular viability. Fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) exhibited an increased abundance of HK2. In a mouse model of bleomycin-induced lung fibrosis, Lonidamine reduced the expression of genes encoding profibrotic markers (collagenΙα1, EDA-fibronectin, α smooth muscle actin, and connective tissue growth factor) and stabilized or improved lung function as assessed by measurement of peripheral blood oxygenation. These findings provide evidence of how metabolic dysregulation through HK2 can be integrated within the context of profibrotic TGF-β signaling. |
| Databáze: | OpenAIRE |
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