Penetration into Cancer Cells via Clathrin-Dependent Mechanism Allows L-Asparaginase from Rhodospirillum rubrum to Inhibit Telomerase

Plyasova, Anna A.; Pokrovskaya, M. V.; Lisitsyna, Olga M.; Pokrovsky, Vadim S.; Alexandrova, S.; Hilal, Abdullah; Соколов, Н. Н.; Zhdanov, Dmitry

doi:10.3390/ph13100286

Cited by 17 publications

(6 citation statements)

References 44 publications

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“…Sodium azide (NaN 3 ) is known to inhibit ATP synthesis and thus inhibit endocytosis because endocytosis is an ATP-dependent process [ 61 ]. We studied the influence of sodium azide on the penetration of sRL2 into A549 cells.…”

Section: Resultsmentioning

confidence: 99%

Uptake of Cell-Penetrating Peptide RL2 by Human Lung Cancer Cells: Monitoring by Electron Paramagnetic Resonance and Confocal Laser Scanning Microscopy

et al. 2021

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RL2 is a recombinant analogue of a human κ-casein fragment, capable of penetrating cells and inducing apoptosis of cancer cells with no toxicity to normal cells. The exact mechanism of RL2 penetration into cells remains unknown. In this study, we investigated the mechanism of RL2 penetration into human lung cancer A549 cells by a combination of electron paramagnetic resonance (EPR) spectroscopy and confocal laser scanning microscopy. EPR spectra of A549 cells incubated with RL2 (sRL2) spin-labeled by a highly stable 3-carboxy-2,2,5,5-tetraethylpyrrolidine-1-oxyl radical were found to contain three components, with their contributions changing with time. The combined EPR and confocal-microscopy data allowed us to assign these three forms of sRL2 to the spin-labeled protein sticking to the membrane of the cell and endosomes, to the spin-labeled protein in the cell interior, and to spin labeled short peptides formed in the cell because of protein digestion. EPR spectroscopy enabled us to follow the kinetics of transformations between different forms of the spin-labeled protein at a minimal spin concentration (3–16 μM) in the cell. The prospects of applications of spin-labeled cell-penetrating peptides to EPR imaging, DNP, and magnetic resonance imaging are discussed, as is possible research on an intrinsically disordered protein in the cell by pulsed dipolar EPR spectroscopy.

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Section: Resultsmentioning

confidence: 99%

Uptake of Cell-Penetrating Peptide RL2 by Human Lung Cancer Cells: Monitoring by Electron Paramagnetic Resonance and Confocal Laser Scanning Microscopy

et al. 2021

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“…Regarding the highest ranked microorganisms associated to early stage colon cancer (Table 3), we have found that, in the case of Rhodospirillum, for instance, it is known to be able to produce molecules such as L-asparaginase which is a regulator of telomerase activity that has been found able to act on human cancer and immune cells (Zhdanov et al, 2017a , b ; Plyasova et al, 2020 ). Nitrosospira is associated with processes related to ammonia oxidation (Kowalchuk and Stephen, 2001 ) in connection with colon cancer (Bingham et al, 1996 ; Bruce et al, 2000 ; Davis and Milner, 2009 ; O'keefe, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Gene-Microbiome Co-expression Networks in Colon Cancer

2021

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It is known that cancer onset and development arise from complex, multi-factorial phenomena spanning from the molecular, functional, micro-environmental, and cellular up to the tissular and organismal levels. Important advances have been made in the systematic analysis of the molecular (mostly genomic and transcriptomic) within large studies of high throughput data such as The Cancer Genome Atlas collaboration. However, the role of the microbiome in the induction of biological changes needed to reach these pathological states remains to be explored, largely because of scarce experimental data. In recent work a non-standard bioinformatics strategy was used to indirectly quantify microbial abundance from TCGA RNA-seq data, allowing the evaluation of the microbiome in well-characterized cancer patients, thus opening the way to studies incorporating the molecular and microbiome dimensions altogether. In this work, we used such recently described approaches for the quantification of microbial species alongside with gene expression. With this, we will reconstruct bipartite networks linking microbial abundance and gene expression in the context of colon cancer, by resorting to network reconstruction based on measures from information theory. The rationale is that microbial communities may induce biological changes important for the cancerous state. We analyzed changes in microbiome-gene interactions in the context of early (stages I and II) and late (stages III and IV) colon cancer, studied changes in network descriptors, and identify key discriminating features for early and late stage colon cancer. We found that early stage bipartite network is associated with the establishment of structural features in the tumor cells, whereas late stage is related to more advance signaling and metabolic features. This functional divergence thus arise as a consequence of changes in the organization of the corresponding gene-microorganism co-expression networks.

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“…More recently, an asparagine-independent cytotoxicity mechanism was reported specifically for a Rodosprillum rubrum mutant L-ASNase [ 83 ]. In contrast to other bacterial L-ASNases, this RrA variant can penetrate cancer cells via a clathrin receptor-dependent manner resulting in suppression of telomerase activity and asparagine-independent cytotoxicity [ 83 , 84 ].…”

Section: Bacterial L-asnase Used In the Clinic For All Therapymentioning

confidence: 99%

Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy

Trimpont

Peeters

Visser

et al. 2022

Cancers

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L-Asparaginase (L-ASNase) is an enzyme that hydrolyses the amino acid asparagine into aspartic acid and ammonia. Systemic administration of bacterial L-ASNase is successfully used to lower the bioavailability of this non-essential amino acid and to eradicate rapidly proliferating cancer cells with a high demand for exogenous asparagine. Currently, it is a cornerstone drug in the treatment of the most common pediatric cancer, acute lymphoblastic leukemia (ALL). Since these lymphoblasts lack the expression of asparagine synthetase (ASNS), these cells depend on the uptake of extracellular asparagine for survival. Interestingly, recent reports have illustrated that L-ASNase may also have clinical potential for the treatment of other aggressive subtypes of hematological or solid cancers. However, immunogenic and other severe adverse side effects limit optimal clinical use and often lead to treatment discontinuation. The design of optimized and novel L-ASNase formulations provides opportunities to overcome these limitations. In addition, identification of multiple L-ASNase resistance mechanisms, including ASNS promoter reactivation and desensitization, has fueled research into promising novel drug combinations to overcome chemoresistance. In this review, we discuss recent insights into L-ASNase adverse effects, resistance both in hematological and solid tumors, and how novel L-ASNase variants and drug combinations can expand its clinical applicability.

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Penetration into Cancer Cells via Clathrin-Dependent Mechanism Allows L-Asparaginase from Rhodospirillum rubrum to Inhibit Telomerase

Cited by 17 publications

References 44 publications

Uptake of Cell-Penetrating Peptide RL2 by Human Lung Cancer Cells: Monitoring by Electron Paramagnetic Resonance and Confocal Laser Scanning Microscopy

Uptake of Cell-Penetrating Peptide RL2 by Human Lung Cancer Cells: Monitoring by Electron Paramagnetic Resonance and Confocal Laser Scanning Microscopy

Gene-Microbiome Co-expression Networks in Colon Cancer

Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy

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