Premium
Comparisons of ATP‐competitive (Type I) versus function‐selective (Type IV) ERK Inhibitors to Prevent Airway Smooth Muscle Cell Proliferation
Author(s) -
Defnet Amy,
Huang Weiliang,
Kane Maureen,
Deshpande Deepak A,
Shapiro Paul
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.793.2
Subject(s) - cell growth , platelet derived growth factor receptor , mapk/erk pathway , microbiology and biotechnology , signal transduction , bronchoconstriction , platelet derived growth factor , cell type , growth factor , activator (genetics) , extracellular , cell , biology , chemistry , cancer research , immunology , biochemistry , receptor , asthma
Hyperproliferation of airway smooth muscle (ASM) cells is a characteristic of airway remodeling associated with inflammatory diseases, such as asthma. Currently, there are no effective therapies to stop ASM cell proliferation that contributes to debilitating bronchoconstriction. Previous studies have shown that stimuli such as growth factors, cytokines, and cellular stress induce signaling through the extracellular signal‐regulated kinases (ERK1/2) in ASM cells making them a potential therapeutic target. Although several Type I selective ATP‐competitive inhibitors of ERK1/2 have been developed, these compounds block all enzymatic activity, including ERK1/2 functions in normal cells not associated with a disease. Given the ubiquitous expression and multiple functions of ERK1/2, the use of ATP‐competitive or catalytic site inhibitors may lead to unwanted off‐target effects. To mitigate off‐target toxicity, we previously identified a novel function‐selective Type IV ERK2 inhibitor, referred to as SF‐3‐030. In the current studies, SF‐3‐030 was compared to a known Type I inhibitor, ulixertinib, in regulating platelet‐derived growth factor (PDGF) induced ASM cell proliferation. We show that both SF‐3‐030 and ulixertinib can prevent PDGF‐mediated proliferation of human ASM cells through the disruption of activator protein‐1 (AP‐1) activity along with the inhibition of several key signaling pathways associated with asthma pathogenesis. SF‐3‐030 inhibited ASM cell proliferation and significantly affected the expression of Fos family and c‐Jun proteins to disrupt AP‐1 downstream activity. Proteomic analysis of PDGF‐stimulated ASM cells showed that SF‐3‐030 regulated a subset of proteins that were affected by ulixertinib. Approximately 40% of all proteins that increased, and 20% of all proteins that decreased after 8 and 24 h were common to both treatments indicating SF‐3‐030 and ulixertinib share overlapping mechanisms of action. Both SF‐3‐030 and ulixertinib inhibited PDGF induced TGF‐β signaling, which plays a role in airway remodeling associated with asthma. Unique to SF‐3‐030 was the inhibition of proinflammatory interleukin‐6, collagens, nuclear factor kappa‐light‐chain‐enhancer of activated B cell (NF‐kB), and the production of nitric oxide and reactive oxygen species that are involved in the pathogenesis of asthma. Overall, ulixertinib inhibited the expression of more proteins than SF‐3‐030 but the total number of proteins whose expression increased with SF‐3‐030 or ulixertinib was similar. These data suggest that Type IV function‐selective inhibition of ERK2 is sufficient to mitigate ASM cell proliferation in asthma while reducing possible off‐target effects seen with Type I ATP‐competitive inhibitors. Support or Funding Information R21AI126492 from the National Institutes of Health This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .