Open AccessInhibition of Aurora Kinase B attenuates fibroblast activation and pulmonary fibrosis
Author(s) -
Kasam Rajesh K,
Ghandikota Sudhir,
Soundararajan Divyalakshmi,
Reddy Geereddy B,
Huang Steven K,
Jegga Anil G,
Madala Satish K
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202012131
Subject(s) - fibroblast , pulmonary fibrosis , cancer research , fibrosis , kinase , microbiology and biotechnology , medicine , chemistry , biology , biochemistry , in vitro
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 TGF α, CTGF , and IGF 1, increase aurora kinase B ( AURKB ) expression and activity in fibroblasts. Mechanistically, we demonstrate that Wilms tumor 1 ( WT 1) is a key transcription factor that mediates TGF α‐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 TGF α is highly dependent on AURKB expression and treating TGF α 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 .