Exploiting S-nitrosylation for cancer therapy: facts and perspectives

2020 ◽  
Vol 477 (19) ◽  
pp. 3649-3672
Author(s):  
Salvatore Rizza ◽  
Giuseppe Filomeni
Keyword(s):  
Nitric Oxide ◽  
Cancer Biology ◽  
Synthetic Lethality ◽  
Current Knowledge ◽  
Tissue Homeostasis ◽  
Loss Of Function ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Insight Into

S-nitrosylation, the post-translational modification of cysteines by nitric oxide, has been implicated in several cellular processes and tissue homeostasis. As a result, alterations in the mechanisms controlling the levels of S-nitrosylated proteins have been found in pathological states. In the last few years, a role in cancer has been proposed, supported by the evidence that various oncoproteins undergo gain- or loss-of-function modifications upon S-nitrosylation. Here, we aim at providing insight into the current knowledge about the role of S-nitrosylation in different aspects of cancer biology and report the main anticancer strategies based on: (i) reducing S-nitrosylation-mediated oncogenic effects, (ii) boosting S-nitrosylation to stimulate cell death, (iii) exploiting S-nitrosylation through synthetic lethality.

scholarly journals New Insight into the Role of Nitric Oxide Pathways in Pancreas

2018 ◽  
Vol 51 (6) ◽  
pp. 167-172 ◽  
Author(s):  
Igor Buchwalow ◽  
Jürgen Schnekenburger ◽  
Vera Samoilova ◽  
Werner Boecker ◽  
Joachim Neumann ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Insight Into

The role of hypoxia in endometrial cancer

2021 ◽  
Vol 22 ◽  
Author(s):  
Yarely M. Salinas-Vera ◽  
Dolores Gallardo-Rincón ◽  
Erika Ruíz-García ◽  
Macrina B. Silva-Cázares ◽  
Carmen Sol de la Peña-Cruz ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cell Survival ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Targeted Therapies ◽  
Current Knowledge ◽  
Vasculogenic Mimicry ◽  
Cellular Processes ◽  
Corpus Uteri

: Endometrial cancer represents the most frequent neoplasia from the corpus uteri, and comprises the 14th leading cause of death in women worldwide. Risk factors that contribute to the disease include early menarche, late menopause, nulliparity, and menopausal hormone use, as well as hypertension and obesity comorbidities. The clinical effectiveness of chemotherapy is variable, suggesting that novel molecular targeted therapies against specific cellular processes associated with the maintenance of cancer cell survival and therapy resistance urged to ameliorate the rates of success in endometrial cancer treatment. In the course of tumor growth, cancer cells must adapt to decreased oxygen availability in the microenvironment by upregulation of hypoxia-inducible factors, which orchestrate the activation of a transcriptional program leading to cell survival. During this adaptative process, the hypoxic cancer cells may acquire invasive and metastatic properties as well as increased cell proliferation and resistance to chemotherapy, enhanced angiogenesis, vasculogenic mimicry, and maintenance of cancer cell stemness, which contribute to more aggressive cancer phenotypes. Several studies have shown that hypoxia-inducible factor 1 alpha (HIF-1α) protein is aberrantly overexpressed in many solid tumors from breast, prostate, ovarian, bladder, colon, brain, and pancreas. Thus, it has been considered an important therapeutic target. Here, we reviewed the current knowledge of the relevant roles of cellular hypoxia mechanisms and HIF-1α functions in diverse processes associated with endometrial cancer progression. In addition, we also summarize the role of microRNAs in the posttranscriptional regulation of protein-encoding genes involved in the hypoxia response in endometrial cancer. Finally, we pointed out the need for urgent targeted therapies to impair the cellular processes activated by hypoxia in the tumor microenvironment.

Functional analysis of the SUMOylation pathway in Drosophila

2008 ◽  
Vol 36 (5) ◽  
pp. 868-873 ◽  
Author(s):  
Ana Talamillo ◽  
Jonatan Sánchez ◽  
Rosa Barrio
Keyword(s):  
Functional Analysis ◽  
Fine Tuning ◽  
Model Systems ◽  
Post Translational Modification ◽  
Reversible Process ◽  
Cellular Processes ◽  
Tuning Mechanism ◽  
Sumo Conjugation

SUMOylation, a reversible process used as a ‘fine-tuning’ mechanism to regulate the role of multiple proteins, is conserved throughout evolution. This post-translational modification affects several cellular processes by the modulation of subcellular localization, activity or stability of a variety of substrates. A growing number of proteins have been identified as targets for SUMOylation, although, for many of them, the role of SUMO conjugation on their function is unknown. The use of model systems might facilitate the study of SUMOylation implications in vivo. In the present paper, we have compiled what is known about SUMOylation in Drosophila melanogaster, where the use of genetics provides new insights on SUMOylation's biological roles.

scholarly journals FOXO3a is stabilized by USP18-mediated de-ISGylation and inhibits TGF-β1-induced fibronectin expression

2019 ◽  
Vol 68 (3) ◽  
pp. 786-791 ◽  
Author(s):  
Ban Wang ◽  
Yanhui Li ◽  
Heather Wang ◽  
Jing Zhao ◽  
Yutong Zhao ◽  
...  
Keyword(s):  
Half Life ◽  
Transforming Growth Factor ◽  
Fibroblast Cells ◽  
Post Translational Modification ◽  
Human Lung Fibroblast ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Fibronectin Expression ◽  
Tgf Β1

FOXO3a belongs to a family of transcription factors characterized by a conserved forkhead box DNA-binding domain. It has been known to regulate various cellular processes including cell proliferation, apoptosis and differentiation. Post-translational modifications of FOXO3a and their roles in the regulation of FOXO3a activity have been well-documented. FOXO3a can be phosphorylated, acetylated and ubiquitinated, however, the ISGylation of FOXO3a has not been reported. Protein overexpression, ISGylation and half-life were measured to determine the post-translational modification of FOXO3a. Human fibroblast cells were treated with transforming growth factor (TGF)-β1 to determine the role of FOXO3a ISGylation in TGF-β1 signaling. FOXO3a’s half-life is around 3.7 hours. Inhibition of the proteasome, not lysosome, extends its half-life. ISGylation, but not ubiquitination of FOXO3a, is increased in the presence of the proteasome inhibitor. Overexpression of ISG15 increases FOXO3a degradation, while overexpression of USP18 stabilizes FOXO3a through de-ISGylation. These results suggest that FOXO3a is degraded in the ISGylation and proteasome system, which can be reversed by USP18, an ISG15-specific deubiquitinase. This study reveals a new molecular mechanism by which ISGylation regulates FOXO3a degradation. Furthermore, we show that the overexpression of FOXO3a attenuated TGF-β1-induced fibronectin expression in human lung fibroblast cells without altering Smad2/3 expression and activation. FOXO3a can be ISGylated, which can regulate FOXO3a stability. USP18/FOXO3a pathway is a potential target for treating TGF-β1-mediated fibrotic diseases such as idiopathic pulmonary fibrosis.

scholarly journals Targeting Epigenetic Dependencies in Solid Tumors: Evolutionary Landscape Beyond Germ Layers Origin

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 682 ◽  
Author(s):  
Francesca Citron ◽  
Linda Fabris
Keyword(s):  
Patient Outcomes ◽  
Chromatin Remodeling ◽  
Cancer Biology ◽  
Poor Prognosis ◽  
Molecular Medicine ◽  
Genomic Alteration ◽  
Clinical Settings ◽  
Cellular Processes ◽  
Improve Patient

Extensive efforts recently witnessed the complexity of cancer biology; however, molecular medicine still lacks the ability to elucidate hidden mechanisms for the maintenance of specific subclasses of rare tumors characterized by the silent onset and a poor prognosis (e.g., ovarian cancer, pancreatic cancer, and glioblastoma). Recent mutational fingerprints of human cancers highlighted genomic alteration occurring on epigenetic modulators. In this scenario, the epigenome dependency of cancer orchestrates a broad range of cellular processes critical for tumorigenesis and tumor progression, possibly mediating escaping mechanisms leading to drug resistance. Indeed, in this review, we discuss the pivotal role of chromatin remodeling in shaping the tumor architecture and modulating tumor fitness in a microenvironment-dependent context. We will also present recent advances in the epigenome targeting, posing a particular emphasis on how this knowledge could be translated into a feasible therapeutic approach to individualize clinical settings and improve patient outcomes.

scholarly journals Inositol 1,4,5-Trisphosphate Receptors in Human Disease: A Comprehensive Update

2020 ◽  
Vol 9 (4) ◽  
pp. 1096
Author(s):  
Jessica Gambardella ◽  
Angela Lombardi ◽  
Marco Bruno Morelli ◽  
John Ferrara ◽  
Gaetano Santulli
Keyword(s):  
Human Disease ◽  
Calcium Release ◽  
Current Knowledge ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Genome Wide ◽  
Inositol 1,4,5 Trisphosphate ◽  
Human Disorders

Inositol 1,4,5-trisphosphate receptors (ITPRs) are intracellular calcium release channels located on the endoplasmic reticulum of virtually every cell. Herein, we are reporting an updated systematic summary of the current knowledge on the functional role of ITPRs in human disorders. Specifically, we are describing the involvement of its loss-of-function and gain-of-function mutations in the pathogenesis of neurological, immunological, cardiovascular, and neoplastic human disease. Recent results from genome-wide association studies are also discussed.

scholarly journals Tissue-Nonspecific Alkaline Phosphatase—A Gatekeeper of Physiological Conditions in Health and a Modulator of Biological Environments in Disease

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1648
Author(s):  
Daniel Liedtke ◽  
Christine Hofmann ◽  
Franz Jakob ◽  
Eva Klopocki ◽  
Stephanie Graser
Keyword(s):  
Alkaline Phosphatase ◽  
Clinical Symptoms ◽  
Current Knowledge ◽  
Systemic Disease ◽  
Loss Of Function ◽  
Inorganic Pyrophosphate ◽  
Wide Range ◽  
Mineralization Processes ◽  
Tissue Nonspecific Alkaline Phosphatase

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5′-phosphate to provide, among others, inorganic phosphate for the mineralization and transportable vitamin B6 molecules. Patients with inherited loss of function mutations in the ALPL gene and consequently altered TNAP activity are suffering from the rare metabolic disease hypophosphatasia (HPP). This systemic disease is mainly characterized by impaired bone and dental mineralization but may also be accompanied by neurological symptoms, like anxiety disorders, seizures, and depression. HPP characteristically affects all ages and shows a wide range of clinical symptoms and disease severity, which results in the classification into different clinical subtypes. This review describes the molecular function of TNAP during the mineralization of bones and teeth, further discusses the current knowledge on the enzyme’s role in the nervous system and in sensory perception. An additional focus is set on the molecular role of TNAP in health and on functional observations reported in common laboratory vertebrate disease models, like rodents and zebrafish.

scholarly journals Dynamic measurement of cytosolic pH and [NO3−] uncovers the role of the vacuolar transporter AtCLCa in cytosolic pH homeostasis

2020 ◽  
Vol 117 (26) ◽  
pp. 15343-15353 ◽  
Author(s):  
Elsa Demes ◽  
Laetitia Besse ◽  
Paloma Cubero-Font ◽  
Béatrice Satiat-Jeunemaitre ◽  
Sébastien Thomine ◽  
...  
Keyword(s):  
Chloride Channel ◽  
Loss Of Function ◽  
Ion Transporters ◽  
Ph Homeostasis ◽  
Cytosolic Ph ◽  
Cellular Processes ◽  
Plasma Membrane Proton Pump ◽  
Cytosolic Acidification

Ion transporters are key players of cellular processes. The mechanistic properties of ion transporters have been well elucidated by biophysical methods. Meanwhile, the understanding of their exact functions in cellular homeostasis is limited by the difficulty of monitoring their activity in vivo. The development of biosensors to track subtle changes in intracellular parameters provides invaluable tools to tackle this challenging issue. AtCLCa (Arabidopsis thalianaChloride Channel a) is a vacuolar NO3−/H+exchanger regulating stomata aperture inA.thaliana. Here, we used a genetically encoded biosensor, ClopHensor, reporting the dynamics of cytosolic anion concentration and pH to monitor the activity of AtCLCa in vivo inArabidopsisguard cells. We first found that ClopHensor is not only a Cl−but also, an NO3−sensor. We were then able to quantify the variations of NO3−and pH in the cytosol. Our data showed that AtCLCa activity modifies cytosolic pH and NO3−. In an AtCLCa loss of function mutant, the cytosolic acidification triggered by extracellular NO3−and the recovery of pH upon treatment with fusicoccin (a fungal toxin that activates the plasma membrane proton pump) are impaired, demonstrating that the transport activity of this vacuolar exchanger has a profound impact on cytosolic homeostasis. This opens a perspective on the function of intracellular transporters of the Chloride Channel (CLC) family in eukaryotes: not only controlling the intraorganelle lumen but also, actively modifying cytosolic conditions.

scholarly journals GlcNAcstatins are nanomolar inhibitors of human O-GlcNAcase inducing cellular hyper-O-GlcNAcylation

2009 ◽  
Vol 420 (2) ◽  
pp. 221-227 ◽  
Author(s):  
Helge C. Dorfmueller ◽  
Vladimir S. Borodkin ◽  
Marianne Schimpl ◽  
Daan M. F. van Aalten
Keyword(s):  
Active Site ◽  
Cell Biology ◽  
Rational Design ◽  
Catalytic Mechanism ◽  
Conserved Residues ◽  
Cellular Processes ◽  
Acetyl Group ◽  
Nanomolar Range ◽  
Insight Into

O-GlcNAcylation is an essential, dynamic and inducible post-translational glycosylation of cytosolic proteins in metazoa and can show interplay with protein phosphorylation. Inhibition of OGA (O-GlcNAcase), the enzyme that removes O-GlcNAc from O-GlcNAcylated proteins, is a useful strategy to probe the role of this modification in a range of cellular processes. In the present study, we report the rational design and evaluation of GlcNAcstatins, a family of potent, competitive and selective inhibitors of human OGA. Kinetic experiments with recombinant human OGA reveal that the GlcNAcstatins are the most potent human OGA inhibitors reported to date, inhibiting the enzyme in the sub-nanomolar to nanomolar range. Modification of the GlcNAcstatin N-acetyl group leads to up to 160-fold selectivity against the human lysosomal hexosaminidases which employ a similar substrate-assisted catalytic mechanism. Mutagenesis studies in a bacterial OGA, guided by the structure of a GlcNAcstatin complex, provides insight into the role of conserved residues in the human OGA active site. GlcNAcstatins are cell-permeant and, at low nanomolar concentrations, effectively modulate intracellular O-GlcNAc levels through inhibition of OGA, in a range of human cell lines. Thus these compounds are potent selective tools to study the cell biology of O-GlcNAc.

Dual Role of Nitric Oxide in Cancer Biology

2010 ◽  
pp. 39-57 ◽  
Author(s):  
Shehla Pervin ◽  
Rajan Singh ◽  
Suvajit Sen ◽  
Gautam Chaudhuri
Keyword(s):  
Nitric Oxide ◽  
Cancer Biology ◽  
Dual Role
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