Inhibition of Aurora Kinase B attenuates fibroblast activation and pulmonary fibrosis
Kasam, Rajesh K; Ghandikota, Sudhir; Soundararajan, Divyalakshmi; Reddy, Geereddy B; Huang, Steven K; Jegga, Anil G; Madala, Satish K
2020-09-07
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Kasam, Rajesh K; Ghandikota, Sudhir; Soundararajan, Divyalakshmi; Reddy, Geereddy B; Huang, Steven K; Jegga, Anil G; Madala, Satish K (2020). "Inhibition of Aurora Kinase B attenuates fibroblast activation and pulmonary fibrosis." EMBO Molecular Medicine 12(9): n/a-n/a.
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.SynopsisFibroblast activation is central for the initiation and maintenance of fibrotic lesions in idiopathic pulmonary fibrosis. Our preclinical study describes the pathological role for AURKB in fibroblast activation and presents a potential therapy for the treatment of pulmonary fibrosis using barasertib.AURKB is upregulated in the lungs of IPF patients and mouse models of pulmonary fibrosis.WT1 binds directly to the promoter of AURKB to upregulates its expression.AURKB functions as a positive regulator of fibroproliferation, myofibroblast survival, and ECM production.In vivo barasertib therapy attenuates TGFα‐and bleomycin‐induced pulmonary fibrosis.Fibroblast activation is central for the initiation and maintenance of fibrotic lesions in idiopathic pulmonary fibrosis. Our preclinical study describes the pathological role for AURKB in fibroblast activation and presents a potential therapy for the treatment of pulmonary fibrosis using barasertib.Publisher
Wiley Periodicals, Inc.
ISSN
1757-4676 1757-4684
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