The protein FoxO3 plays a central role in idiopathic pulmonary fibrosis, according to a study reporting that a therapy that scientists are testing for cancer could rein in the protein.
One of the hallmarks of IPF is overproduction of cells known as fibroblasts and myofibroblasts that alter the structure of lungs, worsening their function. Scientists have yet to attain a full grasp of the molecular mechanisms underlying IPF. But they know that fibroblasts and myofibroblasts play a key role in the lung-structure remodeling involved in the disease.
Scientists also know that several proteins that promote lung tissue scarring, or fibrosis, are involved in myofibroblast overproduction. But they had yet to obtain an understanding of the role that FoxO3 — a molecule involved in lung fibroblast growth — played in scarring.
A team of researchers decided to see what role Fox03 played in lung tissue scarring. They used cells taken from IPF patients and healthy controls and did mice studies.
Their research, “FoxO3 an important player in fibrogenesis and therapeutic target for idiopathic pulmonary fibrosis,” appeared in the journal EMBO Molecular Medicine.
The team discovered lower levels of FoxO3 in IPF patients’ lung fibroblasts than in those of healthy controls.
In addition, they learned that a protein control function known as phosphorylation is revved up in fibroblasts linked to IPF.
Proteins that scientists know are involved in IPF include platelet-derived growth factor (PDGF), insulin-like growth factor 1 (IGF-1) and transforming growth factor-β1 (TGF‐β1).
The researchers discovered that TGF‐β1, PDGF and IGF-1 can decrease FoxO3 levels and increase phosphorylation in cells of healthy controls. The changes convert the cells to a state similar to that seen in IPF.
Another finding was that reducing FoxO3 levels led to normal fibroblasts becoming like IPF fibroblasts.
Similar to what they found in human lung cells, researchers discovered lower levels of FoxO3 and stepped-up phosphorylation in mouse models of IPF.
Experiments with mice that had no FoxO3 showed that lack of the protein reduced the severity of lung fibrosis.
Another finding was that treating the animals with a FoxO3 phosphorylation inhibitor known as UCN-01 led to a reduction in fibroblast characteristics associated with IPF.
The results showed that FoxO3 plays a key role in the development of IPF and that inhibiting it could alleviate IPF.
“FoxO3 is a critical integrator of various growth factor signaling pathways and plays a crucial role in suppression of the phenotypic change from fibroblasts to activated myofibroblasts,” the researchers wrote. “Reactivation of FoxO3 by UCN‐01 reversed the phenotypic change and reverted pulmonary fibrosis. Repurposing of UCN‐01 for the treatment of IPF may offer as novel therapeutic option for this devastating disease.”
UCN-01 is also being tested in Phase 2 trials such as NCT00082017 as a treatment for cancer.
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