Extracellular Prolidase (PEPD) Induces Anabolic Processes through EGFR, β1-integrin, and IGF-1R Signaling Pathways in an Experimental Model of Wounded Fibroblasts

Baszanowska, Weronika; Misiura, Magdalena; Ościłowska, Ilona; Pałka, Jerzy; Miltyk, Wojciech

doi:10.3390/ijms22020942

Cited by 9 publications

(6 citation statements)

References 52 publications

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“…The mechanism of this phenomenon has been attributed to the PEPD-dependent activation of EGFR and downstream signalling proteins [ 13 ]. The results of these studies were confirmed in an experimental model of wound healing in fibroblasts using porcine PEPD [ 14 ] and in experimental inflammation in keratinocytes using recombinant human rhPEPD [ 15 ]. These results suggest that PEPD is especially effective in wound healing in conditions of inflammation.…”

Section: Introductionmentioning

confidence: 81%

Recombinant Human Prolidase (rhPEPD) Induces Wound Healing in Experimental Model of Inflammation through Activation of EGFR Signalling in Fibroblasts

et al. 2023

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The potential of recombinant human prolidase (rhPEPD) to induce wound healing in an experimental model of IL-1β-induced inflammation in human fibroblasts was studied. It was found that rhPEPD significantly increased cell proliferation and viability, as well as the expression of the epidermal growth factor receptor (EGFR) and downstream signaling proteins, such as phosphorylated PI3K, AKT, and mTOR, in the studied model. Moreover, rhPEPD upregulated the expression of the β1 integrin receptor and its downstream signaling proteins, such as p-FAK, Grb2 and p-ERK 1/2. The inhibition of EGFR signaling by gefitinib abolished rhPEPD-dependent functions in an experimental model of inflammation. Subsequent studies showed that rhPEPD augmented collagen biosynthesis in IL-1β-treated fibroblasts as well as in a wound healing model (wound closure/scratch test). Although IL-1β treatment of fibroblasts increased cell migration, rhPEPD significantly enhanced this process. This effect was accompanied by an increase in the activity of MMP-2 and MMP-9, suggesting extracellular matrix (ECM) remodeling during the inflammatory process. The data suggest that rhPEPD may play an important role in EGFR-dependent cell growth in an experimental model of inflammation in human fibroblasts, and this knowledge may be useful for further approaches to the treatment of abnormalities of wound healing and other skin diseases.

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Section: Introductionmentioning

confidence: 81%

Recombinant Human Prolidase (rhPEPD) Induces Wound Healing in Experimental Model of Inflammation through Activation of EGFR Signalling in Fibroblasts

et al. 2023

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“…They have the capability to interact with over 200 signaling proteins, including kinases, phosphatases, transmembrane receptors, enzymes, structural and cytoskeletal proteins, proteins involved in transcriptional control, and proteins associated with apoptosis. Moreover, they have demonstrated effects on the inflammatory process and are involved in the regulation of cell proliferation, differentiation, and metabolism [91][92][93][94][95].…”

Section: Discussionmentioning

confidence: 99%

Exosome Liberation by Human Neutrophils under L-Amino Acid Oxidase of Calloselasma rhodostoma Venom Action

Serrath,

Pontes,

Paloschi

et al. 2023

Toxins

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L-Amino acid oxidase (LAAO) is an enzyme found in snake venom that has multifaceted effects, including the generation of hydrogen peroxide (H2O2) during oxidative reactions, leading to various biological and pharmacological outcomes such as apoptosis, cytotoxicity, modulation of platelet aggregation, hemorrhage, and neutrophil activation. Human neutrophils respond to LAAO by enhancing chemotaxis, and phagocytosis, and releasing reactive oxygen species (ROS) and pro-inflammatory mediators. Exosomes cellular nanovesicles play vital roles in intercellular communication, including immune responses. This study investigates the impact of Calloselasma rhodostoma snake venom-derived LAAO (Cr-LAAO) on human neutrophil exosome release, including activation patterns, exosome formation, and content. Neutrophils isolated from healthy donors were stimulated with Cr-LAAO (100 μg/mL) for 3 h, followed by exosome isolation and analysis. Results show that Cr-LAAO induces the release of exosomes with distinct protein content compared to the negative control. Proteomic analysis reveals proteins related to the regulation of immune responses and blood coagulation. This study uncovers Cr-LAAO’s ability to activate human neutrophils, leading to exosome release and facilitating intercellular communication, offering insights into potential therapeutic approaches for inflammatory and immunological disorders.

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“…DNA biosynthesis of C32 WT and C32 POX− cells was evaluated with the CyQUANT ® Cell Proliferation Assay (Thermo Fisher Scientific, Waltham, MA, USA) according to the previously described procedure [68].…”

Section: Dna Biosynthesis Assaymentioning

confidence: 99%

“…Cell membrane integrity of metformin-treated cells was evaluated by using neutral red uptake (NRU) assay, which was described previously [68]. Cytotoxicity was calculated as a percentage of the control (0 mM of metformin, 100% of intact membranes).…”

Section: Cell Membrane Integrity Assaymentioning

confidence: 99%

Proline Dehydrogenase/Proline Oxidase (PRODH/POX) Is Involved in the Mechanism of Metformin-Induced Apoptosis in C32 Melanoma Cell Line

Ościłowska

Rolkowski

Baszanowska

et al. 2022

IJMS

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The role of proline dehydrogenase/proline oxidase (PRODH/POX) in the mechanism of antineoplastic activity of metformin (MET) was studied in C32 melanoma cells. PRODH/POX is a mitochondrial enzyme-degrading proline that is implicated in the regulation of cancer cell survival/apoptosis. The enzyme is activated by AMP kinase (AMPK). It has been found that MET induced a significant decrease in cell viability and DNA biosynthesis accompanied by an increase in the expressions of AMPK and PRODH/POX in C32 cells. The mechanism for MET-dependent cytotoxicity on C32 cells was found at the level of PRODH/POX-induced ROS generation and activation of Caspase-3 and Caspase-9 expressions in these cells. The effects were not observed in MET-treated PRODH/POX knock-out C32 cells. Of interest is an MET-dependent increase in the concentration of proline, which is a substrate for PRODH/POX. This phenomenon is due to the MET-dependent inhibition of collagen biosynthesis, which is the main proline-utilizing process. It has been found that the underlying mechanism of anticancer activity of MET involves the activation of AMPK, PRODH/POX, increase in the cytoplasmic concentration of proline, inhibition of collagen biosynthesis, and stimulation of PRODH/POX-dependent ROS generation, which initiate the apoptosis of melanoma cells.

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Extracellular Prolidase (PEPD) Induces Anabolic Processes through EGFR, β1-integrin, and IGF-1R Signaling Pathways in an Experimental Model of Wounded Fibroblasts

Cited by 9 publications

References 52 publications

Recombinant Human Prolidase (rhPEPD) Induces Wound Healing in Experimental Model of Inflammation through Activation of EGFR Signalling in Fibroblasts

Recombinant Human Prolidase (rhPEPD) Induces Wound Healing in Experimental Model of Inflammation through Activation of EGFR Signalling in Fibroblasts

Exosome Liberation by Human Neutrophils under L-Amino Acid Oxidase of Calloselasma rhodostoma Venom Action

Proline Dehydrogenase/Proline Oxidase (PRODH/POX) Is Involved in the Mechanism of Metformin-Induced Apoptosis in C32 Melanoma Cell Line

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