2023

Jump to: 2022, 2020

29 pages, 1252 KiB

Open AccessReview

HER3: Toward the Prognostic Significance, Therapeutic Potential, Current Challenges, and Future Therapeutics in Different Types of Cancer

by Avisek Majumder

Cells 2023, 12(21), 2517; https://doi.org/10.3390/cells12212517 - 25 Oct 2023

Cited by 2 | Viewed by 2990

Abstract

Human epidermal growth factor receptor 3 (HER3) is the only family member of the EGRF/HER family of receptor tyrosine kinases that lacks an active kinase domain (KD), which makes it an obligate binding partner with other receptors for its oncogenic role. When HER3 [...] Read more.

Human epidermal growth factor receptor 3 (HER3) is the only family member of the EGRF/HER family of receptor tyrosine kinases that lacks an active kinase domain (KD), which makes it an obligate binding partner with other receptors for its oncogenic role. When HER3 is activated in a ligand-dependent (NRG1/HRG) or independent manner, it can bind to other receptors (the most potent binding partner is HER2) to regulate many biological functions (growth, survival, nutrient sensing, metabolic regulation, etc.) through the PI3K–AKT–mTOR pathway. HER3 has been found to promote tumorigenesis, tumor growth, and drug resistance in different cancer types, especially breast and non-small cell lung cancer. Given its ubiquitous expression across different solid tumors and role in oncogenesis and drug resistance, there has been a long effort to target HER3. As HER3 cannot be targeted through its KD with small-molecule kinase inhibitors via the conventional method, pharmaceutical companies have used various other approaches, including blocking either the ligand-binding domain or extracellular domain for dimerization with other receptors. The development of treatment options with anti-HER3 monoclonal antibodies, bispecific antibodies, and different combination therapies showed limited clinical efficiency for various reasons. Recent reports showed that the extracellular domain of HER3 is not required for its binding with other receptors, which raises doubt about the efforts and applicability of the development of the HER3-antibodies for treatment. Whereas HER3-directed antibody–drug conjugates showed potentiality for treatment, these drugs are still under clinical trial. The currently understood model for dimerization-induced signaling remains incomplete due to the absence of the crystal structure of HER3 signaling complexes, and many lines of evidence suggest that HER family signaling involves more than the interaction of two members. This review article will significantly expand our knowledge of HER3 signaling and shed light on developing a new generation of drugs that have fewer side effects than the current treatment regimen for these patients. Full article

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14 pages, 5320 KiB

Open AccessArticle

Physical Training Chronically Stimulates the Motor Neuron Cell Nucleus in the Ts65Dn Mouse, a Model of Down Syndrome

by Chiara Rita Inguscio, Maria Assunta Lacavalla, Barbara Cisterna, Carlo Zancanaro and Manuela Malatesta

Cells 2023, 12(11), 1488; https://doi.org/10.3390/cells12111488 - 27 May 2023

Viewed by 939

Abstract

Down syndrome (DS) is a genetically-based disease based on the trisomy of chromosome 21 (Hsa21). DS is characterized by intellectual disability in association with several pathological traits among which early aging and altered motor coordination are prominent. Physical training or passive exercise were [...] Read more.

Down syndrome (DS) is a genetically-based disease based on the trisomy of chromosome 21 (Hsa21). DS is characterized by intellectual disability in association with several pathological traits among which early aging and altered motor coordination are prominent. Physical training or passive exercise were found to be useful in counteracting motor impairment in DS subjects. In this study we used the Ts65Dn mouse, a widely accepted animal model of DS, to investigate the ultrastructural architecture of the medullary motor neuron cell nucleus taken as marker of the cell functional state. Using transmission electron microscopy, ultrastructural morphometry, and immunocytochemistry we carried out a detailed investigation of possible trisomy-related alteration(s) of nuclear constituents, which are known to vary their amount and distribution as a function of nuclear activity, as well as the effect of adapted physical training upon them. Results demonstrated that trisomy per se affects nuclear constituents to a limited extent; however, adapted physical training is able to chronically stimulate pre-mRNA transcription and processing activity in motor neuron nuclei of trisomic mice, although to a lesser extent than in their euploid mates. These findings are a step towards understanding the mechanisms underlying the positive effect of physical activity in DS. Full article

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30 pages, 1409 KiB

Open AccessReview

Sex and Brain: The Role of Sex Chromosomes and Hormones in Brain Development and Parkinson’s Disease

by Francesca Terrin, Annachiara Tesoriere, Nicoletta Plotegher and Luisa Dalla Valle

Cells 2023, 12(11), 1486; https://doi.org/10.3390/cells12111486 - 27 May 2023

Cited by 3 | Viewed by 1935

Abstract

Sex hormones and genes on the sex chromosomes are not only key factors in the regulation of sexual differentiation and reproduction but they are also deeply involved in brain homeostasis. Their action is crucial for the development of the brain, which presents different [...] Read more.

Sex hormones and genes on the sex chromosomes are not only key factors in the regulation of sexual differentiation and reproduction but they are also deeply involved in brain homeostasis. Their action is crucial for the development of the brain, which presents different characteristics depending on the sex of individuals. The role of these players in the brain is fundamental in the maintenance of brain function during adulthood as well, thus being important also with respect to age-related neurodegenerative diseases. In this review, we explore the role of biological sex in the development of the brain and analyze its impact on the predisposition toward and the progression of neurodegenerative diseases. In particular, we focus on Parkinson’s disease, a neurodegenerative disorder that has a higher incidence in the male population. We report how sex hormones and genes encoded by the sex chromosomes could protect from the disease or alternatively predispose toward its development. We finally underline the importance of considering sex when studying brain physiology and pathology in cellular and animal models in order to better understand disease etiology and develop novel tailored therapeutic strategies. Full article

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14 pages, 5884 KiB

Open AccessArticle

Temporal Changes in Nuclear Envelope Permeability during Semi-Closed Mitosis in Dictyostelium Amoebae

by Kristina Mitic, Irene Meyer, Ralph Gräf and Marianne Grafe

Cells 2023, 12(10), 1380; https://doi.org/10.3390/cells12101380 - 13 May 2023

Viewed by 1329

Abstract

The Amoebozoan Dictyostelium discoideum exhibits a semi-closed mitosis in which the nuclear membranes remain intact but become permeabilized to allow tubulin and spindle assembly factors to access the nuclear interior. Previous work indicated that this is accomplished at least by partial disassembly of [...] Read more.

The Amoebozoan Dictyostelium discoideum exhibits a semi-closed mitosis in which the nuclear membranes remain intact but become permeabilized to allow tubulin and spindle assembly factors to access the nuclear interior. Previous work indicated that this is accomplished at least by partial disassembly of nuclear pore complexes (NPCs). Further contributions by the insertion process of the duplicating, formerly cytosolic, centrosome into the nuclear envelope and nuclear envelope fenestrations forming around the central spindle during karyokinesis were discussed. We studied the behavior of several Dictyostelium nuclear envelope, centrosomal, and nuclear pore complex (NPC) components tagged with fluorescence markers together with a nuclear permeabilization marker (NLS-TdTomato) by live-cell imaging. We could show that permeabilization of the nuclear envelope during mitosis occurs in synchrony with centrosome insertion into the nuclear envelope and partial disassembly of nuclear pore complexes. Furthermore, centrosome duplication takes place after its insertion into the nuclear envelope and after initiation of permeabilization. Restoration of nuclear envelope integrity usually occurs long after re-assembly of NPCs and cytokinesis has taken place and is accompanied by a concentration of endosomal sorting complex required for transport (ESCRT) components at both sites of nuclear envelope fenestration (centrosome and central spindle). Full article

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14 pages, 2428 KiB

Open AccessArticle

Bacillus subtilis Modulated the Expression of Osteogenic Markers in a Human Osteoblast Cell Line

by Jerry Maria Sojan, Caterina Licini, Fabio Marcheggiani, Oliana Carnevali, Luca Tiano, Monica Mattioli-Belmonte and Francesca Maradonna

Cells 2023, 12(3), 364; https://doi.org/10.3390/cells12030364 - 19 Jan 2023

Cited by 2 | Viewed by 1631

Abstract

Several in vivo trials have previously demonstrated the beneficial effects of the administration of various probiotic forms on bone health. In this study, we explored the potency of two probiotics, Bacillus subtilis and Lactococcus lactis, alone or in combination with vitamin D [...] Read more.

Several in vivo trials have previously demonstrated the beneficial effects of the administration of various probiotic forms on bone health. In this study, we explored the potency of two probiotics, Bacillus subtilis and Lactococcus lactis, alone or in combination with vitamin D (VD), to modulate the transcription of genes involved in the ossification process in a human osteoblast cell line. Genes that mark the “osteoblast proliferation phase”, such as RUNX2, TGFB1, and ALPL, “extracellular matrix (ECM) maturation”, such as SPP1 and SPARC, as well as “ECM mineralization”, such as BGN, BGLAP, and DCN, were all highly expressed in osteoblasts treated with B. subtilis extract. The observed increase in the transcription of the ALPL mRNA was further in agreement with its protein levels as observed by Western blot and immunofluorescence. Therefore, this higher transcription and translation of alkaline phosphatase in osteoblasts treated with the B. subtilis extract, indicated its substantial osteogenic impact on human osteoblasts. Although both the probiotic extracts showed no osteogenic synergy with VD, treatment with B. subtilis alone could increase the ECM mineralization, outperforming the effects of L. lactis and even VD. Furthermore, these results supported the validity of employing probiotic extracts rather than live cells to investigate the effects of probiotics in the in vitro systems. Full article

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2022

Jump to: 2023, 2020

20 pages, 5699 KiB

Open AccessArticle

Histone Citrullination Mediates a Protective Role in Endothelium and Modulates Inflammation

by Rebeca Osca-Verdegal, Jesús Beltrán-García, Ana B. Paes, Elena Nacher-Sendra, Susana Novella, Carlos Hermenegildo, Nieves Carbonell, José Luis García-Giménez and Federico V. Pallardó

Cells 2022, 11(24), 4070; https://doi.org/10.3390/cells11244070 - 15 Dec 2022

Cited by 3 | Viewed by 1628

Abstract

NETosis is a key host immune process against a pathogenic infection during innate immune activation, consisting of a neutrophil “explosion” and, consequently, NET formation, containing mainly DNA, histones, and other nuclear proteins. During sepsis, an exacerbated immune host response to an infection occurs, [...] Read more.

NETosis is a key host immune process against a pathogenic infection during innate immune activation, consisting of a neutrophil “explosion” and, consequently, NET formation, containing mainly DNA, histones, and other nuclear proteins. During sepsis, an exacerbated immune host response to an infection occurs, activating the innate immunity and NETosis events, which requires histone H3 citrullination. Our group compared the circulating histone levels with those citrullinated H3 levels in plasma samples of septic patients. In addition, we demonstrated that citrullinated histones were less cytotoxic for endothelial cells than histones without this post-translational modification. Citrullinated histones did not affect cell viability and did not activate oxidative stress. Nevertheless, citrullinated histones induced an inflammatory response, as well as regulatory endothelial mechanisms. Furthermore, septic patients showed elevated levels of circulating citrullinated histone H3, indicating that the histone citrullination is produced during the first stages of sepsis, probably due to the NETosis process. Full article

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20 pages, 2909 KiB

Open AccessArticle

Reduced SKP2 Expression Adversely Impacts Genome Stability and Promotes Cellular Transformation in Colonic Epithelial Cells

by Nicole M. Neudorf, Laura L. Thompson, Zelda Lichtensztejn, Tooba Razi and Kirk J. McManus

Cells 2022, 11(23), 3731; https://doi.org/10.3390/cells11233731 - 22 Nov 2022

Viewed by 1555

Abstract

Despite the high morbidity and mortality rates associated with colorectal cancer (CRC), the underlying molecular mechanisms driving CRC development remain largely uncharacterized. Chromosome instability (CIN), or ongoing changes in chromosome complements, occurs in ~85% of CRCs and is a proposed driver of cancer [...] Read more.

Despite the high morbidity and mortality rates associated with colorectal cancer (CRC), the underlying molecular mechanisms driving CRC development remain largely uncharacterized. Chromosome instability (CIN), or ongoing changes in chromosome complements, occurs in ~85% of CRCs and is a proposed driver of cancer development, as the genomic changes imparted by CIN enable the acquisition of karyotypes that are favorable for cellular transformation and the classic hallmarks of cancer. Despite these associations, the aberrant genes and proteins driving CIN remain elusive. SKP2 encodes an F-box protein, a variable subunit of the SKP1-CUL1-F-box (SCF) complex that selectively targets proteins for polyubiquitylation and degradation. Recent data have identified the core SCF complex components (SKP1, CUL1, and RBX1) as CIN genes; however, the impact reduced SKP2 expression has on CIN, cellular transformation, and oncogenesis remains unknown. Using both short- small interfering RNA (siRNA) and long-term (CRISPR/Cas9) approaches, we demonstrate that diminished SKP2 expression induces CIN in both malignant and non-malignant colonic epithelial cell contexts. Moreover, temporal assays reveal that reduced SKP2 expression promotes cellular transformation, as demonstrated by enhanced anchorage-independent growth. Collectively, these data identify SKP2 as a novel CIN gene in clinically relevant models and highlight its potential pathogenic role in CRC development. Full article

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15 pages, 2140 KiB

Open AccessArticle

Predicting Progression of Autosomal Dominant Polycystic Kidney Disease by Changes in the Telomeric Epigenome

by Ismail Kocyigit, Serpil Taheri, Cihan Uysal, Mehmet Memis, Salih Guntug Ozayturk, Gokmen Zararsiz and Minoo Rassoulzadegan

Cells 2022, 11(20), 3300; https://doi.org/10.3390/cells11203300 - 20 Oct 2022

Cited by 1 | Viewed by 1528

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of chronic kidney disease with Polycystin (PKD) 1 and 2 gene mutation. However, the intra-familial variability in symptoms further suggests a non-Mendelian contribution to the disease. Our goal was [...] Read more.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of chronic kidney disease with Polycystin (PKD) 1 and 2 gene mutation. However, the intra-familial variability in symptoms further suggests a non-Mendelian contribution to the disease. Our goal was to find a marker to track the epigenetic changes common to rapidly progressing forms of the disease. The risk of ADPKD increases with age, and aging shortens the telomere length (TL). Telomeres are a nucleoprotein structure composed mainly of three complexes, shelterin, CST and RNA-containing telomere repeat(TERRA), which protects the ends of chromosomes from degradation and fusion, and plays a role in maintaining cellular stability and in the repair of telomeric damage. TERRAs are transcribed from telomeric regions and a part of them is engaged in a DNA/RNA hybrid (R-loop) at each chromosome end. We tracked TL and TERRA levels in blood samples of 78 patients and 20 healthy control. Our study demonstrates that TL was shortened and TERRA expression levels in the DNA-attached fraction increased in autosomal dominant polycystic kidney patients with mutations in PKD1 and PKD2 compared to the control group. Moreover, it was observed that the expression of TERRA engaged in the R-loop was higher and the length of telomeres shorter in patients with ADPKD who showed rapid disease progression. Intrafamilial variation in TL and TERRA levels with the same mutation would indicate reliable epigenetic potential biomarkers in disease monitoring. Full article

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2020

Jump to: 2023, 2022

16 pages, 1566 KiB

Open AccessArticle

High Content Screening Using New U2OS Reporter Cell Models Identifies Harmol Hydrochloride as a Selective and Competitive Antagonist of the Androgen Receptor

by Hadjer Dellal, Abdelhay Boulahtouf, Elina Alaterre, Alice Cuenant, Marina Grimaldi, William Bourguet, Céline Gongora, Patrick Balaguer and Philippe Pourquier

Cells 2020, 9(6), 1469; https://doi.org/10.3390/cells9061469 - 16 Jun 2020

Cited by 10 | Viewed by 3218

Abstract

Prostate cancer is the most commonly diagnosed malignancy in men. Its growth mainly relies on the activity of the androgen receptor (AR), justifying the use of androgen deprivation therapy as a gold standard treatment for the metastatic disease. Inhibition of the androgen axis [...] Read more.

Prostate cancer is the most commonly diagnosed malignancy in men. Its growth mainly relies on the activity of the androgen receptor (AR), justifying the use of androgen deprivation therapy as a gold standard treatment for the metastatic disease. Inhibition of the androgen axis using second generation antagonists has improved patients’ survival, but is systematically confronted to resistance mechanisms, leading to a median survival that does not exceed 5 years. Counteracting this resistance has been the object of a large number of investigations, with a particular emphasis towards the identification of new AR inhibitors, whether they antagonize the receptor by a competitive or a non-competitive binding. To this end, many high content screens have been performed, to identify new non-steroidal AR antagonists, using a variety of approaches, but reported somewhat controversial results, depending on the approach and on the cell model that was used for screening. In our study, we used the U2OS osteosarcoma cells stably transfected with AR or ARv7 and a luciferase reporter as a previously validated model to screen the Prestwick Phytochemical library. The results of our screen identified ellipticine, harmol, and harmine hydrochloride as confirmed hits. Surprisingly, we could demonstrate that harmol hydrochloride, previously identified as a non-competitive inhibitor of AR or a weak inhibitor of androgen signaling, was actually a competitive antagonist of AR, which inhibits the growth of VCaP prostate cancer line, at concentrations for which it did not affect the growth of the AR negative DU145 and PC3 cells. Interestingly, we also report for the first time that harmol hydrochloride was selective for AR, as it could not alter the activity of other nuclear receptors, such as the glucocorticoid receptor (GR), the progesterone receptor (PR), or the mineralocorticoid receptor (MR). Additionally, we demonstrate that, conversely to enzalutamide, harmol hydrochloride did not show any agonistic activity towards the pregnane X receptor (PXR), a master regulator of drug metabolism. Together, our results shed light on the importance of the cellular context for the screening of new AR antagonists. They further indicate that some of the potential hits that were previously identified may have been overlooked. Full article

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20 pages, 9513 KiB

Open AccessEditor’s ChoiceArticle

Comparative Application of BioID and TurboID for Protein-Proximity Biotinylation

by Danielle G. May, Kelsey L. Scott, Alexandre R. Campos and Kyle J. Roux

Cells 2020, 9(5), 1070; https://doi.org/10.3390/cells9051070 - 25 Apr 2020

Cited by 81 | Viewed by 21775

Abstract

BioID is a well-established method for identifying protein–protein interactions and has been utilized within live cells and several animal models. However, the conventional labeling period requires 15–18 h for robust biotinylation which may not be ideal for some applications. Recently, two new ligases [...] Read more.

BioID is a well-established method for identifying protein–protein interactions and has been utilized within live cells and several animal models. However, the conventional labeling period requires 15–18 h for robust biotinylation which may not be ideal for some applications. Recently, two new ligases termed TurboID and miniTurbo were developed using directed evolution of the BioID ligase and were able to produce robust biotinylation following a 10 min incubation with excess biotin. However, there is reported concern about inducibility of biotinylation, cellular toxicity, and ligase stability. To further investigate the practical applications of TurboID and ascertain strengths and weaknesses compared to BioID, we developed several stable cell lines expressing BioID and TurboID fusion proteins and analyzed them via immunoblot, immunofluorescence, and biotin-affinity purification-based proteomics. For TurboID we observed signs of protein instability, persistent biotinylation in the absence of exogenous biotin, and an increase in the practical labeling radius. However, TurboID enabled robust biotinylation in the endoplasmic reticulum lumen compared to BioID. Induction of biotinylation could be achieved by combining doxycycline-inducible expression with growth in biotin depleted culture media. These studies should help inform investigators utilizing BioID-based methods as to the appropriate ligase and experimental protocol for their particular needs. Full article

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