Protein phosphatase 2A (PP2A): a key phosphatase in the progression of chronic obstructive pulmonary disease (COPD) to lung cancer

Nader, Cassandra P.; Cidem, Aylin; Verrills, Nicole M.; Ammit, Alaina J.

doi:10.1186/s12931-019-1192-x

Cited by 30 publications

(24 citation statements)

References 191 publications

(318 reference statements)

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“…PP2A activity may represent one such link. As previously mentioned, cigarette smoke increased the level of CTSS via inhibition PP2A, which may function as a tumor suppressor [99,135]. Furthermore, cigarette smoke induced the expression of the oncoprotein CIP2A (cancerous inhibitor of PP2A), which down-regulates PP2A activity and enhances proteolytic responses [136], potentially creating a favorable inflammatory micro-environment that may promote tumor formation.…”

Section: Lung Cancermentioning

confidence: 90%

Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics

et al. 2020

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Dysregulated expression and activity of cathepsin S (CTSS), a lysosomal protease and a member of the cysteine cathepsin protease family, is linked to the pathogenesis of multiple diseases, including a number of conditions affecting the lungs. Extracellular CTSS has potent elastase activity and by processing cytokines and host defense proteins, it also plays a role in the regulation of inflammation. CTSS has also been linked to G-coupled protein receptor activation and possesses an important intracellular role in major histocompatibility complex class II antigen presentation. Modulated CTSS activity is also associated with pulmonary disease comorbidities, such as cancer, cardiovascular disease, and diabetes. CTSS is expressed in a wide variety of immune cells and is biologically active at neutral pH. Herein, we review the significance of CTSS signaling in pulmonary diseases and associated comorbidities. We also discuss CTSS as a plausible therapeutic target and describe recent and current clinical trials examining CTSS inhibition as a means for treatment. Proteases in pulmonary diseases Research in the last 60 years has demonstrated that proteases are critical contributors to pulmonary disease pathophysiology. Initially known as protein-degrading enzymes with a restricted spectrum of substrates, recent studies have revealed that the diversity of protease substrates and biological effects triggered by their processing is vast [1, 2]. Proteases are primarily known for their matrix degradation capabilities, but also play significant roles in other biological mechanisms such as angiogenesis, growth factor bioavailability, cytokine processing, receptor shedding and activation, as well as cellular processes including migration, proliferation, invasion, and survival [3]. Importantly, protease activity requires tight regulation, and disruption of the close interplay between proteases, substrates and inhibitors may contribute to the pathogenesis and progression of a variety of pulmonary diseases, including muco-inflammatory diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), as well as infection [4]. In pulmonary diseases with a high neutrophil burden such as CF, a protease:antiprotease imbalance is frequently observed. The activity of proteases such as neutrophil elastase (NE) in the respiratory tract is regulated by antiproteases, such as α1-antitrypsin (A1AT) [5], secretory leukoprotease inhibitor (SLPI) [6] and elafin [7]. However, in diseases like CF, the antiproteases are overburdened by their cognate proteases and this imbalance can result in chronic airway inflammation, decreased mucociliary clearance, mucus obstruction, extracellular matrix (ECM) remodeling, increased susceptibility to infection and impaired immune responses [8].

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Section: Lung Cancermentioning

confidence: 90%

Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics

et al. 2020

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Section: Discussionmentioning

confidence: 99%

“…PP2A-B55 negatively regulates AKT signaling; therefore, it is referred to as a tumor suppressor [17,18]. PP2A inactivation and AKT activation are the key drivers of cell survival and drug resistance in lung cancer, particularly in NSCLC [17,18]. The cellular PP2A inhibitors oncoprotein I2PP2A (SET) and cancerous inhibitor of PP2A (CIP2A) affect drug resistance and cell survival in many cancers; subsequently, CIP2A downregulation and SET inhibition activate PP2A and restore chemosensitivity to cisplatin as well as reduce tumor burden [17,18].…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, therapeutic strategies targeting PP2A have become increasingly important. PP2A also regulates AKT and NF-κB via the ensuing signaling cascades [12,17]. The downregulation of the AKT/NF-κB pathway is partly associated with cell growth inhibition and apoptosis induction by the soybean isoflavonoid genistein [19,20].…”

Section: Discussionmentioning

confidence: 99%

“…Although the original roles of these proteins were restricted to PV maturation and parasite growth [13], roles in the modulation of host signaling pathways have since been described [13,14]. Furthermore, the anticancer effects of GRA16 reflect the binding of HAUSP and PP2A sites and the resulting regulation of cell cycle progression, proliferation, and apoptosis [10,11,15,17,18]. Herein, we present novel evidence showing that T. gondii GRA16 overcomes the limitations of the commonly used chemotherapeutic agent irinotecan by inhibiting NF-κB activation.…”

Section: Discussionmentioning

confidence: 99%

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Toxoplasma GRA16 Inhibits NF-κB Activation through PP2A-B55 Upregulation in Non-Small-Cell Lung Carcinoma Cells

Seo

Kim

Shin

et al. 2020

IJMS

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Nuclear factor kappa B (NF-κB) activation is a well-known mechanism by which chemoresistance to anticancer agents is reported. It is well-known that irinotecan as a chemotherapeutic drug against non-small-cell lung carcinoma (NSCLC) has limited anticancer effect due to NF-κB activation. In this study, we propose the novel role of GRA16, a dense granule protein of Toxoplasma gondii, as an anticancer agent to increase the effectiveness of chemotherapy via the inhibition of NF-κB activation. To demonstrate this, H1299 cells were stably transfected with GRA16. The anticancer effects of GRA16 were demonstrated as a reduction in tumor size in a mouse xenograft model. GRA16 directly elevated B55 regulatory subunit of protein phosphatase 2A (PP2A-B55) expression in tumor cells, thereby decreasing GWL protein levels and ENSA phosphorylation. This cascade, in turn, induced PP2A-B55 activation and suppressed AKT/ERK phosphorylation and cyclin B1 levels, suggesting reduced cell survival and arrested cell cycle. Moreover, PP2A-B55 activation and AKT phosphorylation inhibition led to NF-κB inactivation via the reduction in inhibitory kappa B kinase beta (IKKβ) levels, de-phosphorylation of inhibitor of kappa B alpha (IκBα), and reduction in the nuclear transit of NF-κB p65. Furthermore, this molecular mechanism was examined under irinotecan treatment. The PP2A-B55/AKT/NF-κB p65 pathway-mediated anticancer effects were only induced in the presence of GRA16, but not in the presence of irinotecan. Moreover, GRA16 synergistically promoted the anticancer effects of irinotecan via the induction of the sub-G1 phase and reduction of cell proliferation. Collectively, irinotecan and GRA16 co-treatment promotes the anticancer effects of irinotecan via NF-κB inhibition and cell cycle arrest induced by GRA16, subsequently increasing the chemotherapeutic effect of irinotecan to NSCLC cells via NF-κB inhibition.

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NXNL1 negatively regulates osteoblast differentiation via GDF15‐induced PP2A Cα dependent manner in MC3T3‐E1 cells

Kim

Jang

2021

BioFactors

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Controlling the level of intracellular reactive oxygen species (ROS) is important for the survival and differentiation of osteoblasts. Intracellular ROS levels are controlled by antioxidant enzymes that modulate the redox state of the cell. Nucleoredoxin-like 1 (NXNL1) is an antioxidant enzyme that increases the viability of rod and cone cells by protecting them from oxidative stress, and is a potential pharmacological target for the treatment of retinitis pigmentosa. The present study investigated the role of NXNL on osteoblast differentiation of MC3T3-E1 preosteoblast cells. Results from qPCR experiments demonstrated that growth differentiation factor 15 (GDF15) increased NXNL1 expression, and that GDF15-induced NXNL1 decreased the expression of osteogenic genes such as distal-less homeobox 5 (Dlx5) and Runt-related transcription factor 2. Furthermore, NXNL1 also inhibits bone morphogenetic protein 2-induced phosphorylation of Smad1/5/9 and alkaline phosphatase activity. The inhibitory effects of NXNL1 on osteoblast differentiation were mediated by protein phosphatase 2A Cα (PP2A Cα). The expression of PP2A Cα was regulated by GDF15, and overexpression of PP2A Cα increased the expression of NXNL1.Taken together, our results demonstrate that NXNL1 inhibits osteoblast differentiation of MC3T3-E1 due to GDF15-induced expression of PP2A Cα.

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Protein phosphatase 2A (PP2A): a key phosphatase in the progression of chronic obstructive pulmonary disease (COPD) to lung cancer

Cited by 30 publications

References 191 publications

Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics

Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics

Toxoplasma GRA16 Inhibits NF-κB Activation through PP2A-B55 Upregulation in Non-Small-Cell Lung Carcinoma Cells

NXNL1 negatively regulates osteoblast differentiation via GDF15‐induced PP2A Cα dependent manner in MC3T3‐E1 cells

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