Proline oxidase silencing induces proline-dependent pro-survival pathways in MCF-7 cells

Zaręba, Ilona; Celińska-Janowicz, Katarzyna; Surażyński, Arkadiusz; Miltyk, Wojciech; Pałka, Jerzy

doi:10.18632/oncotarget.24466

Cited by 13 publications

(27 citation statements)

References 55 publications

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“…One of the characteristic changes accompanying the aging process is the impairment of collagen biosynthesis and its content in tissues 26. To check whether 2nd and 3rd generation PAMAM dendrimers affect this process, we conducted a study on collagen biosynthesis using 5[ 3 H]-proline incorporation.…”

Section: Resultsmentioning

confidence: 99%

<p>Effect of 2nd and 3rd generation PAMAM dendrimers on proliferation, differentiation, and pro-inflammatory cytokines in human keratinocytes and fibroblasts</p>

Czarnomysy¹,

Bielawska²,

Bielawski³

2019

IJN

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Background Poly(amidoamine) (PAMAM) dendrimers are of considerable interest when used as a carrier for topical drugs for the skin, although little is known about their possible side effects. Therefore, our study was about the impact of 2nd and 3rd generation PAMAM dendrimers on human keratinocytes and fibroblasts cells. Methods The effect of the tested compounds on collagen biosynthesis was determined using 5[ 3 H]-proline incorporation bioassay. Morphological changes accompanying cell growth inhibition were observed using a confocal microscope. To evaluate the percentage of apoptotic/necrotic cells and the cell growth dynamic of apoptotic features, we performed Annexin V/PI double staining assay, assessed caspase activity, and performed cell cycle analysis by flow cytometry. The flow cytometry method was also used to determine the effect of dendrimers on pro-inflammatory cytokines (IL-6, IL-8 IL-1β). Results The obtained results showed that as the concentration and the generation of dendrimers increased, collagen biosynthesis decreased. We also observed abnormalities in cell differentiation, which may have caused disturbed secretion of pro-inflammatory cytokines. We found that dendrimers cause chronic inflammation which may cause adverse changes in the skin, ultimately– leading to apoptosis in the case of dendrimers in lower concentrations or necrosis at higher concentrations (especially 3rd generation dendrimers). In addition, the inflammatory path induced by the tested compounds was caused by damage in the mitochondria, which we observed as a significant decrease in the mitochondrial membrane potential. Conclusion The results of our study showed that PAMAM dendrimers can cause disorders of cell proliferation and differentiation and may be the cause of cell cycle deregulation and chronic adverse inflammation.

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Section: Resultsmentioning

confidence: 99%

<p>Effect of 2nd and 3rd generation PAMAM dendrimers on proliferation, differentiation, and pro-inflammatory cytokines in human keratinocytes and fibroblasts</p>

Czarnomysy¹,

Bielawska²,

Bielawski³

2019

IJN

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“…Both intrinsic and extrinsic pathways of apoptosis may be induced by PRODH/POX [42]. Especially, in the extrinsic pathway (death receptor), PRODH/POX stimulates the expression of tumor necrosis factor-related apoptosisactivated ligand (TRAIL), DR5, and cleavage of caspase-8 [42,43], and also activates caspase-9 and caspase-3 [44,45]. In cancer cells, PRODH/POX is upregulated by a variety of factors, for example tumor suppressor p53 and inflammatory factor peroxisome proliferator-activated receptor gamma (PPARγ) [7,10].…”

Section: Prodh/pox-induced Apoptosismentioning

confidence: 99%

“…The recent study of Zareba et al, (2018) showed that in knocked down PRODH/POX MCF-7 breast cancer cells, cytoplasmic proline accumulation induced autophagy. However it was established that environmental conditions such as hypoxia or glucose deficiency may affect PRODH/ POX-dependent autophagy/apoptosis [9].…”

Section: Prodh/pox-induced Autophagymentioning

confidence: 99%

“…The availability of proline in the cell facilitates generation of α-KG that inhibits the transcriptional activity of HIF-1α. An increase in αKG concentration leads to an increase in the activity of a prolyl hydroxylase domain (PHD) of HIF-1α inducing proteasomal degradation of HIF-1α [43,45,54]. In contrast, proline through the same mechanism inhibits the activity of PHD, contributing to a decrease in HIF-1α proteasomal degradation and increase in its transcriptional activity.…”

Section: Prodh/pox-induced Autophagymentioning

confidence: 99%

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Understanding the role of key amino acids in regulation of proline dehydrogenase/proline oxidase (prodh/pox)-dependent apoptosis/autophagy as an approach to targeted cancer therapy

et al. 2020

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In stress conditions, as neoplastic transformation, amino acids serve not only as nutrients to maintain the cell survival but also as mediators of several regulatory pathways which are involved in apoptosis and autophagy. Especially, under glucose deprivation, in order to maintain the cell survival, proline and glutamine together with other glutamine-derived products such as glutamate, alpha-ketoglutarate, and ornithine serve as alternative sources of energy. They are substrates for production of pyrroline-5-carboxylate which is the product of conversion of proline by proline dehydrogenase/ proline oxidase (PRODH/ POX) to produce ATP for protective autophagy or reactive oxygen species for apoptosis. Interconversion of proline, ornithine, and glutamate may therefore regulate PRODH/POX-dependent apoptosis/autophagy. The key amino acid is proline, circulating between mitochondria and cytoplasm in the proline cycle. This shuttle is known as proline cycle. It is coupled to pentose phosphate pathway producing nucleotides for DNA biosynthesis. PRODH/POX is also linked to p53 and AMP-activated protein kinase (AMPK)-dependent pathways. Proline availability for PRODH/POX-dependent apoptosis/autophagy is regulated at the level of collagen biosynthesis (proline utilizing process) and prolidase activity (proline supporting process). In this review, we suggest that amino acid metabolism linking TCA and Urea cycles affect PRODH/POX-dependent apoptosis/ autophagy and the knowledge might be useful to targeted cancer therapy.

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“…An alternative pathway of proline metabolism is its metabolism in the mitochondria, where it undergoes enzymatic conversion to pyrroline‐5‐carboxylic acid by proline oxidase (PRODH/POX). Increased activity of PRODH/POX induces apoptosis, which indicates an important role of proline in the regulation of cellular homeostasis. The functional significance of prolidase is observed in autosomal recessive disease—prolidase deficiency, which disturbs the degradation of proline‐containing imidodipeptides.…”

Section: Collagen As a Source Of Pcpsmentioning

confidence: 99%

Proline‐containing peptides—New insight and implications: A Review

Misiura

Miltyk

2019

BioFactors

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The family of regulatory proline‐containing peptides (PCPs), also known as glyprolines, exhibit significant biological activity. The group of glyprolines includes Gly‐Pro (GP), Pro‐Gly‐Pro (PGP), cyclic Gly‐Pro (cGP), as well as PGP derivatives, for example, N‐acetylated PGP (N‐a‐PGP) and N‐methylated PGP (N‐m‐PGP). PCPs are engaged in various biological processes including the proinflammatory neutrophil chemoattraction in lung diseases, inflammatory bowel diseases or ischemic stroke. Glyprolines have been also postulated to play an important role as atheroprotective and anticoagulant agents, exhibit neuroprotective effects in Parkinson's disease, as well as regulate insulin‐like growth factor (IGF) homeostasis. It was also noticed that PCPs inhibit proliferation and migration of keratinocytes in wound healing, protection of the gastric mucosa and stimulation of its regeneration. The regulatory glyprolines are derived from endogenous and exogenous sources. Most PCPs are derived from collagen or diet protein degradation. Recently, great interest is concentrated on short proline‐rich oligopeptides derived from IGF‐1 degradation. The mechanism of PCPs biological activity is not fully explained. It involves receptor‐mediated mechanisms, for example, N‐a‐PGP acts as CXCR1/2 receptor ligand, whereas cGP regulates IGF‐1 bioavailability by modifying the IGF‐1 binding to the IGF‐1 binding protein‐3. PGP has been observed to interact with collagen‐specific receptors. The data suggest a promising role of PGP as a target of various diseases therapy. This review is focused on the effect of PCPs on metabolic processes in different tissues and the molecular mechanism of their action as an approach to pharmacotherapy of PCPs‐dependent diseases.

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Proline oxidase silencing induces proline-dependent pro-survival pathways in MCF-7 cells

Cited by 13 publications

References 55 publications

<p>Effect of 2nd and 3rd generation PAMAM dendrimers on proliferation, differentiation, and pro-inflammatory cytokines in human keratinocytes and fibroblasts</p>

<p>Effect of 2nd and 3rd generation PAMAM dendrimers on proliferation, differentiation, and pro-inflammatory cytokines in human keratinocytes and fibroblasts</p>

Understanding the role of key amino acids in regulation of proline dehydrogenase/proline oxidase (prodh/pox)-dependent apoptosis/autophagy as an approach to targeted cancer therapy

Proline‐containing peptides—New insight and implications: A Review

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