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Tackling MARCKS‐PIP3 circuit attenuates fibroblast activation and fibrosis progression
- Source :
- FASEB J
- Publication Year :
- 2019
- Publisher :
- Wiley, 2019.
-
Abstract
- Targeting activated fibroblasts, including myofibroblast differentiation, has emerged as a key therapeutic strategy in patients with idiopathic pulmonary fibrosis (IPF). However, there is no available therapy capable of selectively eradicating myofibroblasts or limiting their genesis. Through an integrative analysis of the regulator genes that are responsible for the activation of IPF fibroblasts, we noticed the phosphatidylinositol 4,5-bisphosphate (PIP2)-binding protein, myristoylated alanine-rich C-kinase substrate (MARCKS), as a potential target molecule for IPF. Herein, we have employed a 25-mer novel peptide, MARCKS phosphorylation site domain sequence (MPS), to determine if MARCKS inhibition reduces pulmonary fibrosis through the inactivation of PI3K/protein kinase B (AKT) signaling in fibroblast cells. We first observed that higher levels of MARCKS phosphorylation and the myofibroblast marker α-smooth muscle actin (α-SMA) were notably overexpressed in all tested IPF lung tissues and fibroblast cells. Treatment with the MPS peptide suppressed levels of MARCKS phosphorylation in primary IPF fibroblasts. A kinetic assay confirmed that this peptide binds to phospholipids, particularly PIP2, with a dissociation constant of 17.64 nM. As expected, a decrease of phosphatidylinositol (3,4,5)-trisphosphate pools and AKT activity occurred in MPS-treated IPF fibroblast cells. MPS peptide was demonstrated to impair cell proliferation, invasion, and migration in multiple IPF fibroblast cells in vitro as well as to reduce pulmonary fibrosis in bleomycin-treated mice in vivo. Surprisingly, we found that MPS peptide decreases α-SMA expression and synergistically interacts with nintedanib treatment in IPF fibroblasts. Our data suggest MARCKS as a druggable target in pulmonary fibrosis and also provide a promising antifibrotic agent that may lead to effective IPF treatments.—Yang, D. C., Li, J.-M., Xu, J., Oldham, J., Phan, S. H., Last, J. A., Wu, R., Chen, C.-H. Tackling MARCKS-PIP3 circuit attenuates fibroblast activation and fibrosis progression.
- Subjects :
- Pulmonary Fibrosis
Phosphatidylinositols
Biochemistry
Bleomycin
Mice
chemistry.chemical_compound
Fibrosis
Pulmonary fibrosis
Genetics
medicine
Animals
Humans
MARCKS
Myristoylated Alanine-Rich C Kinase Substrate
Fibroblast
Molecular Biology
Protein kinase B
Cells, Cultured
PI3K/AKT/mTOR pathway
Cell Proliferation
Antibiotics, Antineoplastic
Research
Fibroblasts
respiratory system
medicine.disease
Actins
respiratory tract diseases
medicine.anatomical_structure
Gene Expression Regulation
chemistry
Cancer research
Female
Nintedanib
Proto-Oncogene Proteins c-akt
Myofibroblast
Biotechnology
Subjects
Details
- ISSN :
- 15306860 and 08926638
- Volume :
- 33
- Database :
- OpenAIRE
- Journal :
- The FASEB Journal
- Accession number :
- edsair.doi.dedup.....b1564dc863fb2645534a57f2401c75ff