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Protein Phosphatase 2A as a Therapeutic Target in Pulmonary Diseases
Howard Yu1, Sahil Zaveri1, Zeeshan Sattar1
1Department of Medicine, State University of New York Downstate Health Sciences University, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
Abstract:
New disease targets and medicinal chemistry approaches are urgently needed to develop novel therapeutic strategies for treating pulmonary diseases. Emerging evidence suggests that reduced activity of protein phosphatase 2A (PP2A), a complex heterotrimeric enzyme that regulates dephosphorylation of serine and threonine residues from many proteins, is observed in multiple pulmonary diseases, including lung cancer, smoke-induced chronic obstructive pulmonary disease, alpha-1 antitrypsin deficiency, asthma, and idiopathic pulmonary fibrosis. Loss of PP2A responses is linked to many mechanisms associated with disease progressions, such as senescence, proliferation, inflammation, corticosteroid resistance, enhanced protease responses, and mRNA stability. Therefore, chemical restoration of PP2A may represent a novel treatment for these diseases. This review outlines the potential impact of reduced PP2A activity in pulmonary diseases, endogenous and exogenous inhibitors of PP2A, details the possible PP2A-dependent mechanisms observed in these conditions, and outlines potential therapeutic strategies for treatment. Substantial medicinal chemistry efforts are underway to develop therapeutics targeting PP2A activity. The development of specific activators of PP2A that selectively target PP2A holoenzymes could improve our understanding of the function of PP2A in pulmonary diseases. This may lead to the development of therapeutics for restoring normal PP2A responses within the lung.
Insights
Reduced protein phosphatase 2A (PP2A) activity is linked to various lung diseases. Restoring PP2A function through novel therapeutics offers a promising treatment strategy for pulmonary conditions.
Area of Science:
- Biochemistry
- Pulmonary Medicine
- Pharmacology
Background:
- Reduced protein phosphatase 2A (PP2A) activity is implicated in several pulmonary diseases, including lung cancer, COPD, asthma, and idiopathic pulmonary fibrosis.
- PP2A regulates critical cellular processes, and its diminished function contributes to disease progression mechanisms like senescence, inflammation, and corticosteroid resistance.
Purpose of the Study:
- To review the role of reduced PP2A activity in pulmonary diseases.
- To explore endogenous and exogenous PP2A inhibitors and PP2A-dependent mechanisms.
- To outline potential therapeutic strategies targeting PP2A for lung diseases.
Main Methods:
- Literature review of studies investigating PP2A in pulmonary diseases.
- Analysis of PP2A's role in disease mechanisms.
- Exploration of medicinal chemistry approaches for PP2A modulation.
Main Results:
- Reduced PP2A activity is a common feature across diverse pulmonary conditions.
- Loss of PP2A function is associated with key pathological pathways.
- Medicinal chemistry efforts are focused on developing PP2A activators.
Conclusions:
- Chemical restoration of PP2A activity presents a novel therapeutic avenue for pulmonary diseases.
- Targeting specific PP2A holoenzymes could enhance treatment efficacy.
- Further research into PP2A activators may lead to effective lung disease therapies.
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