Neuropeptide gastrin-releasing peptide induces PI3K/reactive oxygen species–dependent migration in lung adenocarcinoma cells

Jaeger, Natália; Czepielewski, Rafael S.; Bagatini, Maira; Porto, Bárbara Nery; Bonorino, Cristina

doi:10.1177/1010428317694321

Cited by 11 publications

(5 citation statements)

References 58 publications

(86 reference statements)

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“…Therefore, we suggest that the alveolar epithelium is not a target for GRP in order to get a fibrotic response in the lung via EMT. Jaeger and colleagues reported that GRP had no proliferative effect on A549 cells on 24 h after GRP (50 and 100 nM) administration, but it stimulated ROS production and cell migration of these cells [30]. However, it has been shown for the first time that GRP application causes the proliferation of A549 cells in the present study.…”

Section: Discussioncontrasting

confidence: 77%

Gastrin-releasing peptide induces fibrotic response in MRC5s and proliferation in A549s

2020

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Idiopathic pulmonary fibrosis (IPF) is a complex lung disease, whose build-up scar tissue is induced by several molecules. Gastrin-releasing peptide (GRP) is released from pulmonary neuroendocrine cells, alveolar macrophages, and some nerve endings in the lung. A possible role of GRP in IPF is unclear. We aimed to investigate the fibrotic response to GRP, at the cellular level in MRC5 and A549 cell lines. The proliferative and fibrotic effects of GRP on these cells were evaluated by using BrdU, immunoblotting, immunofluorescence and qRT-PCR for molecules associated with myofibroblast differentiation, TGF-β and Wnt signalling. All doses of GRP increased the amount of BrdU incorporation in A549 cells. In contrast, the amount of BrdU increased in MRC5 cells in the first 24 h, though progressively decreased by 72 h. GRP did not stimulate epithelial-mesenchymal transition in A549 cells, rather, it stimulated the differentiation of MRC5 cells into myofibroblasts. Furthermore, GRP induced gene and protein expressions of p-Smad2/3 and Smad4, and reduced the levels of Smad7 in MRC5 cells. In addition, GRP decreased Wnt5a protein levels and stimulated β-catenin activation by increasing Wnt4, Wnt7a and β-catenin protein levels. GRP caused myofibroblast differentiation by inducing TGF-βand Wnt pathways via paracrine and autocrine signalling in MRC5 cells. In conclusion, GRP may lead to pulmonary fibrosis due to its proliferative and fibrotic effects on lung fibroblasts. The abrogation of GRP-mediated signal activation might be considered as a treatment modality for fibrotic lung diseases.

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Section: Discussioncontrasting

confidence: 77%

Gastrin-releasing peptide induces fibrotic response in MRC5s and proliferation in A549s

2020

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“…Thus, the GRK5 KD hampers the autocrine signalling mechanism by inhibiting the expression of both the endogenous ligand as well as that of the corresponding receptor. GRPR is the sole receptor involved in the chemotaxis of cancer cells towards the ligands GRP/bombesin 29,30 . The decrease in its expression by GRK5 KD therefore directly impacts the migration of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of GRK5 hampers the migration of breast cancer cells

Sommer

Falcenberg

Ljepoja

et al. 2019

Sci Rep

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Sunitinib is a multispecific kinase inhibitor and one of its targets is the kinase GRK5, which is regulating a multitude of G protein-coupled receptors (GPCRs). In this study we demonstrate that a decreased GRK5 expression induced by knock-down experiments or sunitinib treatment hampers the migration of cancer cell lines. A proteomic analysis revealed many pathways related to cell migration which were down regulated upon the GRK5 knock-down. Furthermore, we found in MDA-MB-231 breast cancer cells that the inhibition of migration is mediated by the GPCR gastrin releasing peptide receptor (GRPR) leading to a reduced expression of migration regulating downstream targets like CDC42 and ROCK1. An in silico Kaplan Meier analysis revealed that GRK5 and GRPR overexpression reduces the distant metastasis free survival in triple-negative breast cancer (TNBC) patients. Thus, we suggest a novel anti-migratory effect of impaired GRK5 expression which induces a negative feedback loop on GRPR signalling.

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“…In the lung, GRP is produced by specialized epithelial cells, pulmonary neuroendocrine cells, that are activated by neuronally derived γ -aminobutyric acid (GABA) to form clusters called neuroendocrine bodies (NEB) that secrete GRP. GRP binds to its receptor, GRPR (BB2), and activates downstream signal transduction pathways ( e.g ., cAMP, MAPK, PI3K, Akt) ( 93 , 94 ). GRP synergizes with LPS for cytokine production by macrophages ( 82 ).…”

Section: A Central Role For Damp-mediated Tlr4 Signaling In Acute Lung Injury (Ali) Caused By Influenza Infectionmentioning

confidence: 99%

Targeting TLR4 Signaling to Blunt Viral-Mediated Acute Lung Injury

2021

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Respiratory viral infections have been a long-standing global burden ranging from seasonal recurrences to the unexpected pandemics. The yearly hospitalizations from seasonal viruses such as influenza can fluctuate greatly depending on the circulating strain(s) and the congruency with the predicted strains used for the yearly vaccine formulation, which often are not predicted accurately. While antiviral agents are available against influenza, efficacy is limited due to a temporal disconnect between the time of infection and symptom development and viral resistance. Uncontrolled, influenza infections can lead to a severe inflammatory response initiated by pathogen-associated molecular patterns (PAMPs) or host-derived danger-associated molecular patterns (DAMPs) that ultimately signal through pattern recognition receptors (PRRs). Overall, these pathogen-host interactions result in a local cytokine storm leading to acute lung injury (ALI) or the more severe acute respiratory distress syndrome (ARDS) with concomitant systemic involvement and more severe, life threatening consequences. In addition to traditional antiviral treatments, blocking the host’s innate immune response may provide a more viable approach to combat these infectious pathogens. The SARS-CoV-2 pandemic illustrates a critical need for novel treatments to counteract the ALI and ARDS that has caused the deaths of millions worldwide. This review will examine how antagonizing TLR4 signaling has been effective experimentally in ameliorating ALI and lethal infection in challenge models triggered not only by influenza, but also by other ALI-inducing viruses.

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Neuropeptide gastrin-releasing peptide induces PI3K/reactive oxygen species–dependent migration in lung adenocarcinoma cells

Cited by 11 publications

References 58 publications

Gastrin-releasing peptide induces fibrotic response in MRC5s and proliferation in A549s

Gastrin-releasing peptide induces fibrotic response in MRC5s and proliferation in A549s

Downregulation of GRK5 hampers the migration of breast cancer cells

Targeting TLR4 Signaling to Blunt Viral-Mediated Acute Lung Injury

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