Inhibition of Aurora Kinase B attenuates fibroblast activation and pulmonary fibrosis
Abstract Fibroblast activation including proliferation, survival, and ECM production is central to initiation and maintenance of fibrotic lesions in idiopathic pulmonary fibrosis (IPF). However, druggable molecules that target fibroblast activation remain limited. In this study, we show that multipl...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-09-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202012131 |
| _version_ | 1797284907800592384 |
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| author | Rajesh K Kasam Sudhir Ghandikota Divyalakshmi Soundararajan Geereddy B Reddy Steven K Huang Anil G Jegga Satish K Madala |
| author_facet | Rajesh K Kasam Sudhir Ghandikota Divyalakshmi Soundararajan Geereddy B Reddy Steven K Huang Anil G Jegga Satish K Madala |
| author_sort | Rajesh K Kasam |
| collection | DOAJ |
| description | Abstract Fibroblast activation including proliferation, survival, and ECM production is central to initiation and maintenance of fibrotic lesions in idiopathic pulmonary fibrosis (IPF). However, druggable molecules that target fibroblast activation remain limited. In this study, we show that multiple pro‐fibrotic growth factors, including TGFα, CTGF, and IGF1, increase aurora kinase B (AURKB) expression and activity in fibroblasts. Mechanistically, we demonstrate that Wilms tumor 1 (WT1) is a key transcription factor that mediates TGFα‐driven AURKB upregulation in fibroblasts. Importantly, we found that inhibition of AURKB expression or activity is sufficient to attenuate fibroblast activation. We show that fibrosis induced by TGFα is highly dependent on AURKB expression and treating TGFα mice with barasertib, an AURKB inhibitor, reverses fibroblast activation, and pulmonary fibrosis. Barasertib similarly attenuated fibrosis in the bleomycin model of pulmonary fibrosis. Together, our preclinical studies provide important proof‐of‐concept that demonstrate barasertib as a possible intervention therapy for IPF. |
| first_indexed | 2024-03-07T17:54:32Z |
| format | Article |
| id | doaj.art-2a97e233e5134721ba0d532a1b18172e |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:54:32Z |
| publishDate | 2020-09-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-2a97e233e5134721ba0d532a1b18172e2024-03-02T12:42:52ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-09-01129n/an/a10.15252/emmm.202012131Inhibition of Aurora Kinase B attenuates fibroblast activation and pulmonary fibrosisRajesh K Kasam0Sudhir Ghandikota1Divyalakshmi Soundararajan2Geereddy B Reddy3Steven K Huang4Anil G Jegga5Satish K Madala6Division of Pulmonary Medicine Cincinnati Children's Hospital Medical Center Cincinnati OH USADivision of Biomedical Informatics Cincinnati Children's Hospital Medical Center Cincinnati OH USADivision of Pulmonary Medicine Cincinnati Children's Hospital Medical Center Cincinnati OH USADepartment of Biochemistry National Institute of Nutrition Hyderabad IndiaDivision of Pulmonary and Critical Care Medicine Department of Internal Medicine University of Michigan Medical School Ann Arbor MI USADivision of Biomedical Informatics Cincinnati Children's Hospital Medical Center Cincinnati OH USADivision of Pulmonary Medicine Cincinnati Children's Hospital Medical Center Cincinnati OH USAAbstract Fibroblast activation including proliferation, survival, and ECM production is central to initiation and maintenance of fibrotic lesions in idiopathic pulmonary fibrosis (IPF). However, druggable molecules that target fibroblast activation remain limited. In this study, we show that multiple pro‐fibrotic growth factors, including TGFα, CTGF, and IGF1, increase aurora kinase B (AURKB) expression and activity in fibroblasts. Mechanistically, we demonstrate that Wilms tumor 1 (WT1) is a key transcription factor that mediates TGFα‐driven AURKB upregulation in fibroblasts. Importantly, we found that inhibition of AURKB expression or activity is sufficient to attenuate fibroblast activation. We show that fibrosis induced by TGFα is highly dependent on AURKB expression and treating TGFα mice with barasertib, an AURKB inhibitor, reverses fibroblast activation, and pulmonary fibrosis. Barasertib similarly attenuated fibrosis in the bleomycin model of pulmonary fibrosis. Together, our preclinical studies provide important proof‐of‐concept that demonstrate barasertib as a possible intervention therapy for IPF.https://doi.org/10.15252/emmm.202012131Aurora Kinase BBarasertibfibroproliferationpulmonary fibrosisWilms’ tumor 1 |
| spellingShingle | Rajesh K Kasam Sudhir Ghandikota Divyalakshmi Soundararajan Geereddy B Reddy Steven K Huang Anil G Jegga Satish K Madala Inhibition of Aurora Kinase B attenuates fibroblast activation and pulmonary fibrosis EMBO Molecular Medicine Aurora Kinase B Barasertib fibroproliferation pulmonary fibrosis Wilms’ tumor 1 |
| title | Inhibition of Aurora Kinase B attenuates fibroblast activation and pulmonary fibrosis |
| title_full | Inhibition of Aurora Kinase B attenuates fibroblast activation and pulmonary fibrosis |
| title_fullStr | Inhibition of Aurora Kinase B attenuates fibroblast activation and pulmonary fibrosis |
| title_full_unstemmed | Inhibition of Aurora Kinase B attenuates fibroblast activation and pulmonary fibrosis |
| title_short | Inhibition of Aurora Kinase B attenuates fibroblast activation and pulmonary fibrosis |
| title_sort | inhibition of aurora kinase b attenuates fibroblast activation and pulmonary fibrosis |
| topic | Aurora Kinase B Barasertib fibroproliferation pulmonary fibrosis Wilms’ tumor 1 |
| url | https://doi.org/10.15252/emmm.202012131 |
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