138 results on '"Giuseppe Filomeni"'
Search Results
2. TRAP1 S-nitrosylation as a model of population-shift mechanism to study the effects of nitric oxide on redox-sensitive oncoproteins
- Author
-
Elena Papaleo, Matteo Tiberti, Matteo Arnaudi, Chiara Pecorari, Fiorella Faienza, Lisa Cantwell, Kristine Degn, Francesca Pacello, Andrea Battistoni, Matteo Lambrughi, and Giuseppe Filomeni
- Subjects
Cytology ,QH573-671 - Abstract
Abstract S-nitrosylation is a post-translational modification in which nitric oxide (NO) binds to the thiol group of cysteine, generating an S-nitrosothiol (SNO) adduct. S-nitrosylation has different physiological roles, and its alteration has also been linked to a growing list of pathologies, including cancer. SNO can affect the function and stability of different proteins, such as the mitochondrial chaperone TRAP1. Interestingly, the SNO site (C501) of TRAP1 is in the proximity of another cysteine (C527). This feature suggests that the S-nitrosylated C501 could engage in a disulfide bridge with C527 in TRAP1, resembling the well-known ability of S-nitrosylated cysteines to resolve in disulfide bridge with vicinal cysteines. We used enhanced sampling simulations and in-vitro biochemical assays to address the structural mechanisms induced by TRAP1 S-nitrosylation. We showed that the SNO site induces conformational changes in the proximal cysteine and favors conformations suitable for disulfide bridge formation. We explored 4172 known S-nitrosylated proteins using high-throughput structural analyses. Furthermore, we used a coarse-grained model for 44 protein targets to account for protein flexibility. This resulted in the identification of up to 1248 proximal cysteines, which could sense the redox state of the SNO site, opening new perspectives on the biological effects of redox switches. In addition, we devised two bioinformatic workflows ( https://github.com/ELELAB/SNO_investigation_pipelines ) to identify proximal or vicinal cysteines for a SNO site with accompanying structural annotations. Finally, we analyzed mutations in tumor suppressors or oncogenes in connection with the conformational switch induced by S-nitrosylation. We classified the variants as neutral, stabilizing, or destabilizing for the propensity to be S-nitrosylated and undergo the population-shift mechanism. The methods applied here provide a comprehensive toolkit for future high-throughput studies of new protein candidates, variant classification, and a rich data source for the research community in the NO field.
- Published
- 2023
- Full Text
- View/download PDF
3. Autophagy guards tendon homeostasis
- Author
-
Costanza Montagna, Rene B. Svensson, Monika L. Bayer, Salvatore Rizza, Emiliano Maiani, Ching-Yan Chloé Yeung, Giuseppe Filomeni, and Michael Kjær
- Subjects
Cytology ,QH573-671 - Abstract
Abstract Tendons are vital collagen-dense specialized connective tissues transducing the force from skeletal muscle to the bone, thus enabling movement of the human body. Tendon cells adjust matrix turnover in response to physiological tissue loading and pathological overloading (tendinopathy). Nevertheless, the regulation of tendon matrix quality control is still poorly understood and the pathogenesis of tendinopathy is presently unsolved. Autophagy, the major mechanism of degradation and recycling of cellular components, plays a fundamental role in the homeostasis of several tissues. Here, we investigate the contribution of autophagy to human tendons’ physiology, and we provide in vivo evidence that it is an active process in human tendon tissue. We show that selective autophagy of the endoplasmic reticulum (ER-phagy), regulates the secretion of type I procollagen (PC1), the major component of tendon extracellular matrix. Pharmacological activation of autophagy by inhibition of mTOR pathway alters the ultrastructural morphology of three-dimensional tissue-engineered tendons, shifting collagen fibrils size distribution. Moreover, autophagy induction negatively affects the biomechanical properties of the tissue-engineered tendons, causing a reduction in mechanical strength under tensile force. Overall, our results provide the first evidence that autophagy regulates tendon homeostasis by controlling PC1 quality control, thus potentially playing a role in the development of injured tendons.
- Published
- 2022
- Full Text
- View/download PDF
4. GSNOR deficiency promotes tumor growth via FAK1 S-nitrosylation
- Author
-
Salvatore Rizza, Luca Di Leo, Chiara Pecorari, Paola Giglio, Fiorella Faienza, Costanza Montagna, Emiliano Maiani, Michele Puglia, Francesca M. Bosisio, Trine Skov Petersen, Lin Lin, Vendela Rissler, Juan Salamanca Viloria, Yonglun Luo, Elena Papaleo, Daniela De Zio, Blagoy Blagoev, and Giuseppe Filomeni
- Subjects
CP: Cancer ,CP: Molecular biology ,Biology (General) ,QH301-705.5 - Abstract
Summary: Nitric oxide (NO) production in the tumor microenvironment is a common element in cancer. S-nitrosylation, the post-translational modification of cysteines by NO, is emerging as a key transduction mechanism sustaining tumorigenesis. However, most oncoproteins that are regulated by S-nitrosylation are still unknown. Here we show that S-nitrosoglutathione reductase (GSNOR), the enzyme that deactivates S-nitrosylation, is hypo-expressed in several human malignancies. Using multiple tumor models, we demonstrate that GSNOR deficiency induces S-nitrosylation of focal adhesion kinase 1 (FAK1) at C658. This event enhances FAK1 autophosphorylation and sustains tumorigenicity by providing cancer cells with the ability to survive in suspension (evade anoikis). In line with these results, GSNOR-deficient tumor models are highly susceptible to treatment with FAK1 inhibitors. Altogether, our findings advance our understanding of the oncogenic role of S-nitrosylation, define GSNOR as a tumor suppressor, and point to GSNOR hypo-expression as a therapeutically exploitable vulnerability in cancer.
- Published
- 2023
- Full Text
- View/download PDF
5. Loss of Ambra1 promotes melanoma growth and invasion
- Author
-
Luca Di Leo, Valérie Bodemeyer, Francesca M. Bosisio, Giuseppina Claps, Marco Carretta, Salvatore Rizza, Fiorella Faienza, Alex Frias, Shawez Khan, Matteo Bordi, Maria P. Pacheco, Julie Di Martino, Jose J. Bravo-Cordero, Colin J. Daniel, Rosalie C. Sears, Marco Donia, Daniel H. Madsen, Per Guldberg, Giuseppe Filomeni, Thomas Sauter, Caroline Robert, Daniela De Zio, and Francesco Cecconi
- Subjects
Science - Abstract
The absence of scaffold protein Ambra1 leads to hyperproliferation and growth in mouse models. Here the authors show that Ambra1 deficiency accelerates melanoma growth and increases metastasis in mouse models of melanoma through FAK1 hyperactivation.
- Published
- 2021
- Full Text
- View/download PDF
6. Nitric oxide-based regulation of metabolism: Hints from TRAP1 and SIRT3 crosstalk
- Author
-
Fiorella Faienza, Andrea Rasola, and Giuseppe Filomeni
- Subjects
nitric oxide ,metabolism ,mitochondria ,SDH ,nitrosylation ,Biology (General) ,QH301-705.5 - Published
- 2022
- Full Text
- View/download PDF
7. Redox proteome analysis of auranofin exposed ovarian cancer cells (A2780)
- Author
-
Giovanni Chiappetta, Tania Gamberi, Fiorella Faienza, Xhesika Limaj, Salvatore Rizza, Luigi Messori, Giuseppe Filomeni, Alessandra Modesti, and Joelle Vinh
- Subjects
Redox proteomics ,Cysteine ,Auranofin ,Gold drugs ,Ovarian cancer ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
The effects of Auranofin (AF) on protein expression and protein oxidation in A2780 cancer cells were investigated through a strategy based on simultaneous expression proteomics and redox proteomics determinations. Bioinformatics analysis of the proteomics data supports the view that the most critical cellular changes elicited by AF treatment consist of thioredoxin reductase inhibition, alteration of the cell redox state, impairment of the mitochondrial functions, metabolic changes associated with conversion to a glycolytic phenotype, induction of ER stress. The occurrence of the above cellular changes was extensively validated by performing direct biochemical assays. Our data are consistent with the concept that AF produces its effects through a multitarget mechanism that mainly affects the redox metabolism and the mitochondrial functions and results into severe ER stress. Results are discussed in the context of the current mechanistic knowledge existing on AF.
- Published
- 2022
- Full Text
- View/download PDF
8. Screening of metabolic modulators identifies new strategies to target metabolic reprogramming in melanoma
- Author
-
Cecilie Abildgaard, Salvatore Rizza, Helle Christiansen, Steffen Schmidt, Christina Dahl, Ahmad Abdul-Al, Annette Christensen, Giuseppe Filomeni, and Per Guldberg
- Subjects
Medicine ,Science - Abstract
Abstract The prognosis of metastatic melanoma remains poor due to de novo or acquired resistance to immune and targeted therapies. Previous studies have shown that melanoma cells have perturbed metabolism and that cellular metabolic pathways represent potential therapeutic targets. To support the discovery of new drug candidates for melanoma, we examined 180 metabolic modulators, including phytochemicals and anti-diabetic compounds, for their growth-inhibitory activities against melanoma cells, alone and in combination with the BRAF inhibitor vemurafenib. Two positive hits from this screen, 4-methylumbelliferone (4-MU) and ursolic acid (UA), were subjected to validation and further characterization. Metabolic analysis showed that 4-MU affected cellular metabolism through inhibition of glycolysis and enhanced the effect of vemurafenib to reduce the growth of melanoma cells. In contrast, UA reduced mitochondrial respiration, accompanied by an increase in the glycolytic rate. This metabolic switch potentiated the growth-inhibitory effect of the pyruvate dehydrogenase kinase inhibitor dichloroacetate. Both drug combinations led to increased production of reactive oxygen species, suggesting the involvement of oxidative stress in the cellular response. These results support the potential use of metabolic modulators for combination therapies in cancer and may encourage preclinical validation and clinical testing of such treatment strategies in patients with metastatic melanoma.
- Published
- 2021
- Full Text
- View/download PDF
9. Use of Computational Biochemistry for Elucidating Molecular Mechanisms of Nitric Oxide Synthase
- Author
-
Emmanuelle Bignon, Salvatore Rizza, Giuseppe Filomeni, and Elena Papaleo
- Subjects
Biotechnology ,TP248.13-248.65 - Abstract
Nitric oxide (NO) is an essential signaling molecule in the regulation of multiple cellular processes. It is endogenously synthesized by NO synthase (NOS) as the product of L-arginine oxidation to L-citrulline, requiring NADPH, molecular oxygen, and a pterin cofactor. Two NOS isoforms are constitutively present in cells, nNOS and eNOS, and a third is inducible (iNOS). Despite their biological relevance, the details of their complex structural features and reactivity mechanisms are still unclear. In this review, we summarized the contribution of computational biochemistry to research on NOS molecular mechanisms. We described in detail its use in studying aspects of structure, dynamics and reactivity. We also focus on the numerous outstanding questions in the field that could benefit from more extensive computational investigations. Keywords: Nitric oxide synthase, computational methods, molecular mechanisms, redox regulation
- Published
- 2019
- Full Text
- View/download PDF
10. TRAP1: A Metabolic Hub Linking Aging Pathophysiology to Mitochondrial S-Nitrosylation
- Author
-
Fiorella Faienza, Salvatore Rizza, Paola Giglio, and Giuseppe Filomeni
- Subjects
tumor necrosis factor receptor-associated protein 1 (TRAP1) ,S-nitrosylation ,mitochondria ,aging ,cancer ,Parkinson's disease ,Physiology ,QP1-981 - Published
- 2020
- Full Text
- View/download PDF
11. Role, Targets and Regulation of (de)nitrosylation in Malignancy
- Author
-
Salvatore Rizza and Giuseppe Filomeni
- Subjects
ADH5 ,GSNOR ,nitric oxide ,NOS ,nitrosylation ,cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2018
- Full Text
- View/download PDF
12. Editorial: Redox and Metabolic Circuits in Cancer
- Author
-
Salvatore Rizza, Andrea Rasola, Danyelle M. Townsend, and Giuseppe Filomeni
- Subjects
cancer metabolism ,redox signaling ,tumorigenesis ,cancer progression ,reactive oxygen species ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2018
- Full Text
- View/download PDF
13. Mature Erythrocytes of Iguana iguana (Squamata, Iguanidae) Possess Functional Mitochondria.
- Author
-
Giuseppina Di Giacomo, Silvia Campello, Mauro Corrado, Livia Di Giambattista, Claudia Cirotti, Giuseppe Filomeni, and Gabriele Gentile
- Subjects
Medicine ,Science - Abstract
Electron microscopy analyses of Iguana iguana blood preparations revealed the presence of mitochondria within erythrocytes with well-structured cristae. Fluorescence microscopy analyses upon incubation with phalloidin-FITC, Hoechst 33342 and mitochondrial transmembrane potential (Δψm)-sensitive probe MitoTracker Red indicated that mitochondria i) widely occur in erythrocytes, ii) are polarized, and iii) seem to be preferentially confined at a "perinuclear" region, as confirmed by electron microscopy. The analysis of NADH-dependent oxygen consumption showed that red blood cells retain the capability to consume oxygen, thereby providing compelling evidence that mitochondria of Iguana erythrocytes are functional and capable to perform oxidative phosphorylation.
- Published
- 2015
- Full Text
- View/download PDF
14. S-Nitrosoglutathione Reductase Plays Opposite Roles in SH-SY5Y Models of Parkinson’s Disease and Amyotrophic Lateral Sclerosis
- Author
-
Salvatore Rizza, Claudia Cirotti, Costanza Montagna, Simone Cardaci, Claudia Consales, Mauro Cozzolino, Maria Teresa Carrì, Francesco Cecconi, and Giuseppe Filomeni
- Subjects
Pathology ,RB1-214 - Abstract
Oxidative and nitrosative stresses have been reported as detrimental phenomena concurring to the onset of several neurodegenerative diseases. Here we reported that the ectopic modulation of the denitrosylating enzyme S-nitrosoglutathione reductase (GSNOR) differently impinges on the phenotype of two SH-SY5Y-based in vitro models of neurodegeneration, namely, Parkinson’s disease (PD) and familial amyotrophic lateral sclerosis (fALS). In particular, we provide evidence that GSNOR-knocking down protects SH-SY5Y against PD toxins, while, by contrast, its upregulation is required for G93A-SOD1 expressing cells resistance to NO-releasing drugs. Although completely opposite, both conditions are characterized by Nrf2 localization in the nuclear compartment: in the first case induced by GSNOR silencing, while in the second one underlying the antinitrosative response. Overall, our results demonstrate that GSNOR expression has different effect on neuronal viability in dependence on the stimulus applied and suggest that GSNOR could be a responsive gene downstream of Nrf2 activation.
- Published
- 2015
- Full Text
- View/download PDF
15. S-Nitrosation and Ubiquitin-Proteasome System Interplay in Neuromuscular Disorders
- Author
-
Salvatore Rizza, Costanza Montagna, Giuseppina Di Giacomo, Claudia Cirotti, and Giuseppe Filomeni
- Subjects
Cytology ,QH573-671 - Abstract
Protein S-nitrosation is deemed as a prototype of posttranslational modifications governing cell signaling. It takes place on specific cysteine residues that covalently incorporate a nitric oxide (NO) moiety to form S-nitrosothiol derivatives and depends on the ratio between NO produced by NO synthases and nitrosothiol removal catalyzed by denitrosating enzymes. A large number of cysteine-containing proteins are found to undergo S-nitrosation and, among them, the enzymes catalyzing ubiquitination, mainly the class of ubiquitin E3 ligases and the 20S component of the proteasome, have been reported to be redox modulated in their activity. In this review we will outline the processes regulating S-nitrosation and try to debate whether and how it affects protein ubiquitination and degradation via the proteasome. In particular, since muscle and neuronal health largely depends on the balance between protein synthesis and breakdown, here we will discuss the impact of S-nitrosation in the efficiency of protein quality control system, providing lines of evidence and speculating about its involvement in the onset and maintenance of neuromuscular dysfunctions.
- Published
- 2014
- Full Text
- View/download PDF
16. Redox Status and Bioenergetics Liaison in Cancer and Neurodegeneration
- Author
-
Giuseppe Filomeni, Juan P. Bolaños, and Pier Giorgio Mastroberardino
- Subjects
Cytology ,QH573-671 - Published
- 2012
- Full Text
- View/download PDF
17. Established Principles and Emerging Concepts on the Interplay between Mitochondrial Physiology and S-(De)nitrosylation: Implications in Cancer and Neurodegeneration
- Author
-
Giuseppina Di Giacomo, Salvatore Rizza, Costanza Montagna, and Giuseppe Filomeni
- Subjects
Cytology ,QH573-671 - Abstract
S-nitrosylation is a posttranslational modification of cysteine residues that has been frequently indicated as potential molecular mechanism governing cell response upon redox unbalance downstream of nitric oxide (over)production. In the last years, increased levels of S-nitrosothiols (SNOs) have been tightly associated with the onset of nitroxidative stress-based pathologies (e.g., cancer and neurodegeneration), conditions in which alterations of mitochondrial homeostasis and activation of cellular processes dependent on it have been reported as well. In this paper we aim at summarizing the current knowledge of mitochondria-related proteins undergoing S-nitrosylation and how this redox modification might impact on mitochondrial functions, whose impairment has been correlated to tumorigenesis and neuronal cell death. In particular, emphasis will be given to the possible, but still neglected implication of denitrosylation reactions in the modulation of mitochondrial SNOs and how they can affect mitochondrion-related cellular process, such as oxidative phosphorylation, mitochondrial dynamics, and mitophagy.
- Published
- 2012
- Full Text
- View/download PDF
18. Figure S3 from S-nitrosylation of the Mitochondrial Chaperone TRAP1 Sensitizes Hepatocellular Carcinoma Cells to Inhibitors of Succinate Dehydrogenase
- Author
-
Giuseppe Filomeni, Francesco Cecconi, Jonathan S. Stamler, Daniela De Zio, Andrea Rasola, Blagoy Blagoev, Virginia Sanchez-Quiles, Giuseppina Di Giacomo, Emiliano Maiani, Simone Cardaci, Costanza Montagna, and Salvatore Rizza
- Abstract
SDH-generated superoxide is the upstream mediator of α-TOS-induced cell death in siGSNOR HepG2 cells.
- Published
- 2023
19. Supplementary Figure 6 from Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1
- Author
-
Maria Rosa Ciriolo, Giuseppe Rotilio, Maurizio Paci, Maurizio Mattei, Fabio Bertocchi, Roberta Bernardini, Giuseppe Filomeni, Salvatore Rizza, and Simone Cardaci
- Abstract
PDF file - 77K, Glutamine-deprivation up-regulates MCT-1 levels
- Published
- 2023
20. Supplementary figures legends from S-nitrosylation of the Mitochondrial Chaperone TRAP1 Sensitizes Hepatocellular Carcinoma Cells to Inhibitors of Succinate Dehydrogenase
- Author
-
Giuseppe Filomeni, Francesco Cecconi, Jonathan S. Stamler, Daniela De Zio, Andrea Rasola, Blagoy Blagoev, Virginia Sanchez-Quiles, Giuseppina Di Giacomo, Emiliano Maiani, Simone Cardaci, Costanza Montagna, and Salvatore Rizza
- Abstract
Supplementary figures legends
- Published
- 2023
21. Supplementary table 1 from S-nitrosylation of the Mitochondrial Chaperone TRAP1 Sensitizes Hepatocellular Carcinoma Cells to Inhibitors of Succinate Dehydrogenase
- Author
-
Giuseppe Filomeni, Francesco Cecconi, Jonathan S. Stamler, Daniela De Zio, Andrea Rasola, Blagoy Blagoev, Virginia Sanchez-Quiles, Giuseppina Di Giacomo, Emiliano Maiani, Simone Cardaci, Costanza Montagna, and Salvatore Rizza
- Abstract
WB densitometry and statistical analyses
- Published
- 2023
22. Supplementary Figure 5 from Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1
- Author
-
Maria Rosa Ciriolo, Giuseppe Rotilio, Maurizio Paci, Maurizio Mattei, Fabio Bertocchi, Roberta Bernardini, Giuseppe Filomeni, Salvatore Rizza, and Simone Cardaci
- Abstract
PDF file - 98K, Complex II inhibition is responsible for 3-BrPA-induced metabolic-oxidative stress upon glutamine deprivation
- Published
- 2023
23. Supplementary Figure 7 from Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1
- Author
-
Maria Rosa Ciriolo, Giuseppe Rotilio, Maurizio Paci, Maurizio Mattei, Fabio Bertocchi, Roberta Bernardini, Giuseppe Filomeni, Salvatore Rizza, and Simone Cardaci
- Abstract
PDF file - 180K, MCT-1 up-regulation induced by glutamine deprivation is responsible for 3-BrPA chemo-potentiation
- Published
- 2023
24. Data from Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1
- Author
-
Maria Rosa Ciriolo, Giuseppe Rotilio, Maurizio Paci, Maurizio Mattei, Fabio Bertocchi, Roberta Bernardini, Giuseppe Filomeni, Salvatore Rizza, and Simone Cardaci
- Abstract
Anticancer drug efficacy might be leveraged by strategies to target certain biochemical adaptations of tumors. Here we show how depriving cancer cells of glutamine can enhance the anticancer properties of 3-bromopyruvate, a halogenated analog of pyruvic acid. Glutamine deprival potentiated 3-bromopyruvate chemotherapy by increasing the stability of the monocarboxylate transporter-1, an effect that sensitized cells to metabolic oxidative stress and autophagic cell death. We further elucidated mechanisms through which resistance to chemopotentiation by glutamine deprival could be circumvented. Overall, our findings offer a preclinical proof-of-concept for how to employ 3-bromopyruvate or other monocarboxylic-based drugs to sensitize tumors to chemotherapy. Cancer Res; 72(17); 4526–36. ©2012 AACR.
- Published
- 2023
25. Supplementary Figure Legends 1-9, Methods from Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1
- Author
-
Maria Rosa Ciriolo, Giuseppe Rotilio, Maurizio Paci, Maurizio Mattei, Fabio Bertocchi, Roberta Bernardini, Giuseppe Filomeni, Salvatore Rizza, and Simone Cardaci
- Abstract
PDF file - 211K
- Published
- 2023
26. Supplementary Figure 2 from Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1
- Author
-
Maria Rosa Ciriolo, Giuseppe Rotilio, Maurizio Paci, Maurizio Mattei, Fabio Bertocchi, Roberta Bernardini, Giuseppe Filomeni, Salvatore Rizza, and Simone Cardaci
- Abstract
PDF file - 147K, Autophagy contributes to the execution of 3-BrPA-induced cell death upon glutamine withdrawal
- Published
- 2023
27. Supplementary Figure 3 from Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1
- Author
-
Maria Rosa Ciriolo, Giuseppe Rotilio, Maurizio Paci, Maurizio Mattei, Fabio Bertocchi, Roberta Bernardini, Giuseppe Filomeni, Salvatore Rizza, and Simone Cardaci
- Abstract
PDF file - 154K, Glutamine deprivation-induced 3-BrPA chemo-potentiation does not depend on synergistic impairment of glutaminolysis and glycolysis
- Published
- 2023
28. Supplementary materials and methods from S-nitrosylation of the Mitochondrial Chaperone TRAP1 Sensitizes Hepatocellular Carcinoma Cells to Inhibitors of Succinate Dehydrogenase
- Author
-
Giuseppe Filomeni, Francesco Cecconi, Jonathan S. Stamler, Daniela De Zio, Andrea Rasola, Blagoy Blagoev, Virginia Sanchez-Quiles, Giuseppina Di Giacomo, Emiliano Maiani, Simone Cardaci, Costanza Montagna, and Salvatore Rizza
- Abstract
Supplementary materials and methods
- Published
- 2023
29. Supplementary Figure 1 from Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1
- Author
-
Maria Rosa Ciriolo, Giuseppe Rotilio, Maurizio Paci, Maurizio Mattei, Fabio Bertocchi, Roberta Bernardini, Giuseppe Filomeni, Salvatore Rizza, and Simone Cardaci
- Abstract
PDF file - 127K, Chemo-potentiation of 3-BrPA cytotoxicity is not associated with the activation of apoptosis
- Published
- 2023
30. Supplementary Figure 4 from Glutamine Deprivation Enhances Antitumor Activity of 3-Bromopyruvate through the Stabilization of Monocarboxylate Transporter-1
- Author
-
Maria Rosa Ciriolo, Giuseppe Rotilio, Maurizio Paci, Maurizio Mattei, Fabio Bertocchi, Roberta Bernardini, Giuseppe Filomeni, Salvatore Rizza, and Simone Cardaci
- Abstract
PDF file - 55K, Increased oxidative stress underlies 3-BrPA chemo-potentiation induced by glutamine-deprivation
- Published
- 2023
31. GSNOR safeguards S-phase entry and genomic stability in rhabdomyosarcoma cells: unraveling new molecular players
- Author
-
Paola Giglio, Giovanni Larotondo, Chiara Pecorari, Emiliano Maiani, Salvatore Rizza, Giuseppe Filomeni, and Costanza Montagna
- Subjects
Physiology (medical) ,Biochemistry - Published
- 2023
32. Targeting GSNOR deficiency as a new therapeutic approach in rhabdomyosarcoma
- Author
-
Giovanni Larotondo, Paola Giglio, Gianmarco Matrullo, Emiliano Maiani, Giuseppe Filomeni, and Costanza Montagna
- Subjects
Physiology (medical) ,Biochemistry - Published
- 2023
33. WITHDRAWN: Editorial Title: Exploring the Nuances of Nitric Oxide in Cancer
- Author
-
Sharon A. Glynn and Giuseppe Filomeni
- Subjects
Cancer Research ,Physiology ,Clinical Biochemistry ,Biochemistry - Published
- 2023
34. S-nitrosoglutathione reductase (GSNOR) downregulation in Breast Cancer: a possible involvement of miRNAs in controlling GSNOR expression
- Author
-
Gianmarco Matrullo, Valeria Fiorentini, Costanza Montagna, Giuseppe Filomeni, and Salvatore Rizza
- Subjects
Physiology (medical) ,Biochemistry - Published
- 2023
35. AKR1A1 controls redox and metabolic adaptation of renal and hepatocellular carcinoma
- Author
-
Chiara Pecorari, Salvatore Rizza, and Giuseppe Filomeni
- Subjects
Physiology (medical) ,Biochemistry - Published
- 2023
36. Regulation of redox signaling in HIF‐1‐dependent tumor angiogenesis
- Author
-
Valeria Manuelli, Chiara Pecorari, Giuseppe Filomeni, and Ester Zito
- Subjects
ER stress ,ERO1 ,HIF-1 ,UPR ,angiogenesis ,hypoxia ,metastasis ,Angiogenic Switch ,Angiogenesis ,medicine.disease_cause ,Biochemistry ,Metastasis ,Neoplasms ,medicine ,Humans ,Settore BIO/10 ,Molecular Biology ,Transcription factor ,Neovascularization, Pathologic ,Chemistry ,Cell Biology ,Hypoxia-Inducible Factor 1, alpha Subunit ,medicine.disease ,Cell biology ,Oxygen ,Crosstalk (biology) ,medicine.anatomical_structure ,Unfolded protein response ,Hypoxia-Inducible Factor 1 ,Carcinogenesis ,Oxidation-Reduction ,Blood vessel - Abstract
Angiogenesis is the process of blood vessel growth. The angiogenic switch consists of new blood vessel formation that, in carcinogenesis, can lead to the transition from a harmless cluster of dormant cells to a large tumorigenic mass with metastatic potential. Hypoxia, i.e. the scarcity of oxygen, is a hallmark of solid tumors to which they adapt by activating hypoxia-inducible factor-1 (HIF-1), a transcription factor triggering de novo angiogenesis. HIF-1 and the angiogenic molecules that are expressed upon its activation are modulated by redox status. Modulations of the redox environment can influence the angiogenesis signaling at different levels, thereby impinging on the angiogenic switch. This review provides a molecular overview of the redox-sensitive steps in angiogenic signaling, the main molecular players involved and their crosstalk with the unfolded protein response (UPR). New classes of inhibitors of these modulators which might act as antiangiogenic drugs in cancer are also discussed.
- Published
- 2021
37. Looking at denitrosylation to understand the myogenesis gone awry theory of rhabdomyosarcoma
- Author
-
Costanza Montagna and Giuseppe Filomeni
- Subjects
Cancer Research ,S-Nitrosothiols ,Physiology ,Rhabdomyosarcoma ,Clinical Biochemistry ,Humans ,Proteins ,Settore BIO/10 ,Child ,Muscle Development ,Nitric Oxide ,Protein Processing, Post-Translational ,Biochemistry - Abstract
S-nitrosylation of proteins is a nitric oxide (NO)-based post-translational modification of cysteine residues. By removing the NO moiety from S-nitrosothiol adducts, denitrosylases restore sulfhydryl protein pool and act as downstream tuners of S-nitrosylation signaling. Alterations in the S-nitrosylation/denitrosylation dynamics are implicated in many pathological states, including cancer ontogenesis and progression, skeletal muscle myogenesis and function. Here, we aim to provide and link different lines of evidence, and elaborate on the possible role of S-nitrosylation/denitrosylation signaling in rhabdomyosarcoma, one of the most common pediatric mesenchymal malignancy.
- Published
- 2022
38. Exploiting S-nitrosylation for cancer therapy: facts and perspectives
- Author
-
Salvatore Rizza and Giuseppe Filomeni
- Subjects
Programmed cell death ,Cancer therapy ,Synthetic lethality ,Biology ,chemotherapy ,Nitric Oxide ,Biochemistry ,Nitric oxide ,chemistry.chemical_compound ,Neoplasms ,medicine ,cancer ,Humans ,Cancer biology ,Settore BIO/10 ,Molecular Biology ,Tissue homeostasis ,Cell Death ,Cancer ,nitric oxide signaling ,Cell Biology ,S-Nitrosylation ,medicine.disease ,S-nitrosylation ,chemistry ,Protein Processing, Post-Translational ,Neuroscience - Abstract
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.
- Published
- 2020
39. WhenS-Nitrosylation Gets to Mitochondria: From Signaling to Age-Related Diseases
- Author
-
Salvatore Rizza, Giuseppe Filomeni, Costanza Montagna, and Claudia Cirotti
- Subjects
0301 basic medicine ,Physiology ,Coenzyme A ,Clinical Biochemistry ,Cellular homeostasis ,Mitochondrion ,Biology ,Biochemistry ,GSNOR ,cancer ,metabolism ,mitophagy ,neurodegeneration ,03 medical and health sciences ,chemistry.chemical_compound ,Mitophagy ,medicine ,Settore BIO/10 ,Molecular Biology ,General Environmental Science ,030102 biochemistry & molecular biology ,Mechanism (biology) ,Neurodegeneration ,Cell Biology ,S-Nitrosylation ,medicine.disease ,030104 developmental biology ,chemistry ,General Earth and Planetary Sciences ,Neuroscience ,Function (biology) - Abstract
Significance: Cysteines have an essential role in redox signaling, transforming an oxidant signal into a biological response. Among reversible cysteine post-translational modifications, S-nitrosylation acts as a redox-switch in several pathophysiological states, such as ischemia/reperfusion, synaptic transmission, cancer, and muscular dysfunctions. Recent Advances: Growing pieces of in vitro and in vivo evidence argue for S-nitrosylation being deeply involved in development and aging, and playing a role in the onset of different pathological states. New findings suggest it being an enzymatically regulated cellular process, with deep impact on mitochondrial structure and function, and in cellular metabolism. In light of this, the recent discovery of the denitrosylase S-nitrosoCoA (coenzyme A) reductase takes on even greater importance and opens new perspectives on S-nitrosylation as a general mechanism of cellular homeostasis. Critical Issues: Based on these recent findings, we aim at summarizing and elaborating on the established and emerging crucial roles of S-nitrosylation in mitochondrial metabolism and mitophagy, and provide an overview of the pathophysiological effects induced by its deregulation. Future Directions: The identification of new S-nitrosylation targets, and the comprehension of the mechanisms through which S-nitrosylation modulates specific classes of proteins, that is, those impinging on diverse mitochondrial functions, may help to better understand the pathophysiology of aging, and propose lines of intervention to slow down or extend the onset of aging-related diseases.
- Published
- 2020
40. Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue
- Author
-
Marco Rosina, Veronica Ceci, Riccardo Turchi, Chuan Li, Nicholas Borcherding, Francesca Sciarretta, María Sánchez-Díaz, Flavia Tortolici, Keaton Karlinsey, Valerio Chiurchiù, Claudia Fuoco, Rocky Giwa, Rachael L. Field, Matteo Audano, Simona Arena, Alessandro Palma, Federica Riccio, Farnaz Shamsi, Giovanni Renzone, Martina Verri, Anna Crescenzi, Salvatore Rizza, Fiorella Faienza, Giuseppe Filomeni, Sander Kooijman, Stefano Rufini, Antoine A.F. de Vries, Andrea Scaloni, Nico Mitro, Yu-Hua Tseng, Andrés Hidalgo, Beiyan Zhou, Jonathan R. Brestoff, Katia Aquilano, Daniele Lettieri-Barbato, European Foundation for the Study of Diabetes, Boehringer Ingelheim Fonds, Fondation Leducq, Ministerio de Ciencia e Innovación (España), and Fundación La Caixa
- Subjects
brown adipocytes ,thermogenesis ,Physiology ,mitochondrial quality control ,Macrophages ,immunometabolism ,Thermogenesis ,Cell Biology ,Settore BIO/09 ,Mitochondria ,adipose tissue ,macrophages ,mitochondria ,Adipocytes, Brown ,Adipose Tissue, Brown ,homeostasis ,Settore BIO/10 ,extracellular vesicles ,Molecular Biology ,Uncoupling Protein 1 - Abstract
Recent findings have demonstrated that mitochondria can be transferred between cells to control metabolic homeostasis. Although the mitochondria of brown adipocytes comprise a large component of the cell volume and undergo reorganization to sustain thermogenesis, it remains unclear whether an intercellular mitochondrial transfer occurs in brown adipose tissue (BAT) and regulates adaptive thermogenesis. Herein, we demonstrated that thermogenically stressed brown adipocytes release extracellular vesicles (EVs) that contain oxidatively damaged mitochondrial parts to avoid failure of the thermogenic program. When re-uptaken by parental brown adipocytes, mitochondria-derived EVs reduced peroxisome proliferator-activated receptor-γ signaling and the levels of mitochondrial proteins, including UCP1. Their removal via the phagocytic activity of BAT-resident macrophages is instrumental in preserving BAT physiology. Depletion of macrophages in vivo causes the abnormal accumulation of extracellular mitochondrial vesicles in BAT, impairing the thermogenic response to cold exposure. These findings reveal a homeostatic role of tissue-resident macrophages in the mitochondrial quality control of BAT. This work was partially supported by the European Foundation for the Study of Diabetes (EFSD/Lilly, 2017 and EFSD/Boehringer Ingelheim European Research Programme on ‘‘Multi-System Challenges in Diabetes’’) and the Italian Ministry of Health (GR-2018-12367588) to D.L.-B.; Associazione Italiana per la Ricerca sul Cancro (AIRC) under IG 2019 - ID. 23562 project to K.A.; MIUR ‘‘Progetto Eccellenza’’ to Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita` degli Studi di Milano, and NUTRAGE (CNR FOE 2019, DSB.AD004.271) to A.S; Italian Foundation of Multiple Sclerosis (grant 2017/R/8), the Italian Ministry of Health (grant GR-2016-02362380) and the MAI Award grant to V. Chiurchiu; National Institutes of Health (NIH) common fund (DP5 OD028125) and the Burroughs Wellcome Fund (1019648) to J.R.B.; NIH K01DK125608 to F.S.; R01DK102898 and R01DK122808 to Y.- H.T.; and NIH RO1 DK121805 and AHA 19TPA34910079 to B.Z. A.H. was supported by RTI2018-095497-B-I00 from MICINN, HR17_00527 from La Caixa Foundation, and TNE-18CVD04 from the Leducq Foundation. M.S-D was supported by a fellowship PRE2019-08746 from the Ministerio de Ciencia e Innovacio´ n. M.R. was partially supported by a fellowship from AIRC (IG 2019 - ID. 23562) and by the Italian Ministry of Health (SG-2019-12368589). V.C. is part of the PhD Program in Evolutionary Biology and Ecology, Department of Biology, University of Rome Tor Vergata. Sí
- Published
- 2022
41. Nitric oxide-based regulation of metabolism:Hints from TRAP1 and SIRT3 crosstalk
- Author
-
Fiorella Faienza, Andrea Rasola, and Giuseppe Filomeni
- Subjects
CYTOCHROME-C-OXIDASE ,ENZYME ,nitrosylation ,INHIBITION ,SDH ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Biochemistry ,MECHANISMS ,mitochondria ,DEHYDROGENASE ,RESPIRATION ,nitric oxide ,SIRTUINS ,ANTIOXIDANT ,MITOCHONDRIAL CHAPERONE TRAP1 ,GROWTH ,metabolism ,Settore BIO/10 ,Molecular Biology - Published
- 2022
42. Use of Computational Biochemistry for Elucidating Molecular Mechanisms of Nitric Oxide Synthase
- Author
-
Salvatore Rizza, Emmanuelle Bignon, Elena Papaleo, and Giuseppe Filomeni
- Subjects
lcsh:Biotechnology ,molecular mechanisms ,Biophysics ,Review Article ,Biochemistry ,Cofactor ,Nitric oxide ,redox regulation ,computational methods ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Structural Biology ,Enos ,Nos isoforms ,Nitric oxide synthase ,lcsh:TP248.13-248.65 ,Genetics ,Settore BIO/10 ,Pterin ,030304 developmental biology ,0303 health sciences ,biology ,biology.organism_classification ,Computer Science Applications ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,Molecular oxygen ,Computational biochemistry ,Biotechnology - Abstract
Nitric oxide (NO) is an essential signaling molecule in the regulation of multiple cellular processes. It is endogenously synthesized by NO synthase (NOS) as the product of L-arginine oxidation to L-citrulline, requiring NADPH, molecular oxygen, and a pterin cofactor. Two NOS isoforms are constitutively present in cells, nNOS and eNOS, and a third is inducible (iNOS). Despite their biological relevance, the details of their complex structural features and reactivity mechanisms are still unclear. In this review, we summarized the contribution of computational biochemistry to research on NOS molecular mechanisms. We described in detail its use in studying aspects of structure, dynamics and reactivity. We also focus on the numerous outstanding questions in the field that could benefit from more extensive computational investigations., Graphical Abstract Unlabelled Image
- Published
- 2019
43. Hyperbaric exposure and oxidative stress in occupational activities (HEOxS): the study protocol
- Author
-
Katia, Aquilano, Tiziana Paola Baccolo, Bersani, Alberto Maria, Matteo, Bordi, FLAVIA BUONAURIO, Rita Businaro, Cerocchi, Chiara, Corrado, Costanzo, Nazzareno De Angelis, Ornella De Pità, Maria Concetta D’Ovidio, Luigi Fattorini, Giuseppe, Filomeni, Cristian, Ieno, Lettieri Barbato, Daniele, Maggi, Elisa, Enrico, Marchetti, Maria Rosaria Marchetti, Paola, Melis, Alfredo Miccheli, OTTAVIA GIAMPAOLI, Enrico, Paci, Daniela, Pigini, Alessandro Pinto, Floriana, Sacco, Fabio, Sciubba, Mariangela, Spagnoli, Aurora, Summa, Alberta, Tomassini, Elisa Tosti, M., Giovanna, Tranfo, Riccardo, Turchi, and Giuliana Valente, .
- Subjects
hyperbaric exposure ,Hyperbaric exposure ,Oxidative Stress ,Diet Habits ,Fitness ,Cytokines ,Metabolomics ,oxidative stress ,cytokines ,metabolomics ,diet habits ,fitness - Abstract
Background: Hyperbaric exposure (HE) is proven to be a stressor to several mechanisms in living cells. Even if after homeostasis restoration, harmful effects are expected, in particular a presence of free radicals. These latter are the stimulus to negative phenomenon as inflammation or cancer. In Italy, with 7500 km of sea shores, a large quantity of workers is exposed to HE during occupational activities. A deep knowledge of HE and bodily effects is not well defined; hence a multidisciplinary assessment of risk is needed. To detect one or more indicators of HE a research group is organised, under the INAIL sponsorship. The research project focused on the oxidative stress (OxS) and this paper details on the possible protocol to estimate, with a large amount of techniques on several human liquids, the relationship between OxS and HE. Specific attention will be paid to identify confounding factors and their influence. Methods: Blood and urine will be sampled. Several lab techniques will be performed on samples, both targeted, to measure the level of well-known biomarkers, and untargeted. Regard the formers: products of oxidation of DNA and RNA in urine; inflammation and temperature cytokines and protein carbonyles in blood. Untargeted evaluation will be performed for a metabolomics analysis in urine. Confounding factors: temperature, body fat, fitness, allergies and dietary habits. These factors will be assessed, directly or indirectly, prior and after HE. The final scope of the project is to determine one or more indicators that relates to HE in hits twofold nature: depth and duration. Conclusion: The relationship between OxS and HE is not deeply investigated and literature proposes diverging results. The project aims to define the time dependence of biomarkers related to OxS, to rise knowledge in risk assessment in workers exposed to HE.
- Published
- 2021
44. The interplay between mitochondrial functionality and genome integrity in the prevention of human neurologic diseases
- Author
-
Eugenia Dogliotti, Giuseppe Filomeni, Barbara Pascucci, Eleonora Parlanti, Mariarosaria D’Errico, and Pier Giorgio Mastroberardino
- Subjects
0301 basic medicine ,DNA Repair ,Disease ,Mitochondrion ,Biochemistry ,Mitochondrial Dynamics ,Models ,Amyotrophic lateral sclerosis ,Oxidatively induced DNA damage ,Genome ,Neurodegeneration ,Mitophagy ,Neurodegenerative Diseases ,Phenotype ,Mitochondrial ,Mitochondria ,genome integrity ,Neurological ,Metabolic Networks and Pathways ,Human ,DNA repair ,DNA damage ,Models, Neurological ,Biophysics ,DNA damage Response ,Neuropathology ,Biology ,DNA, Mitochondrial ,Genomic Instability ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,medicine ,Humans ,Settore BIO/10 ,DNA repair Defective syndromes ,Molecular Biology ,030102 biochemistry & molecular biology ,Genome, Human ,Mitochondrial dysfunction ,Neurodegenerative diseases ,DNA Damage ,Genome, Mitochondrial ,Mutation ,Reactive Oxygen Species ,DNA ,medicine.disease ,neurologic diseases ,030104 developmental biology ,mitochondrial functionality ,Neuroscience - Abstract
As mitochondria are vulnerable to oxidative damage and represent the main source of reactive oxygen species (ROS), they are considered key tuners of ROS metabolism and buffering, whose dysfunction can progressively impact neuronal networks and disease. Defects in DNA repair and DNA damage response (DDR) may also affect neuronal health and lead to neuropathology. A number of congenital DNA repair and DDR defective syndromes, indeed, show neurological phenotypes, and a growing body of evidence indicate that defects in the mechanisms that control genome stability in neurons acts as aging-related modifiers of common neurodegenerative diseases such as Alzheimer, Parkinson's, Huntington diseases and Amyotrophic Lateral Sclerosis. In this review we elaborate on the established principles and recent concepts supporting the hypothesis that deficiencies in either DNA repair or DDR might contribute to neurodegeneration via mechanisms involving mitochondrial dysfunction/deranged metabolism.
- Published
- 2021
45. AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity
- Author
-
Armando Bartolazzi, Marilena Raciti, Valentina Cianfanelli, Jiri Bartek, Rosalie C. Sears, Rikke Darling Rasmussen, Elena Papaleo, Jirina Bartkova, Guillermo Velasco, Miriam Di Marco, Robert E. Hynds, Francesco Russo, Petra Hamerlik, Salvatore Rizza, Emanuela Pupo, Cristiano De Stefanis, Franco Locatelli, Charles Swanton, Joanna Maria Merchut-Maya, Michele Pagano, Daniele Simoneschi, Søs Grønbæk Holdgaard, Letizia Lanzetti, Gergely Róna, Giacomo Milletti, Nélida Salvador, Giuseppe Filomeni, Luca Di Leo, Daniela De Zio, Francesca Nazio, Colin J. Daniel, Apolinar Maya-Mendoza, Alfie O’sullivan, Estibaliz Gabicagogeascoa, Angela Gallo, Francesco Cecconi, Silvia Campello, Matteo Bordi, Costanza Montagna, Yeon Tae Jeong, Valeriana Cesarini, David R. Pearce, Mar Lorente, Emiliano Maiani, Pasquale D’Acunzo, Marianna Carinci, Maiani, Emiliano, Milletti, Giacomo, Nazio, Francesca, Holdgaard, Søs Grønbæk, Bartkova, Jirina, Rizza, Salvatore, Cianfanelli, Valentina, Lorente, Mar, Simoneschi, Daniele, Di Marco, Miriam, D'Acunzo, Pasquale, Di Leo, Luca, Rasmussen, Rikke, Montagna, Costanza, Raciti, Marilena, De Stefanis, Cristiano, Gabicagogeascoa, Estibaliz, Rona, Gergely, Salvador, Nélida, Pupo, Emanuela, Merchut-Maya, Joanna Maria, Daniel, Colin J, Carinci, Marianna, Cesarini, Valeriana, O'Sullivan, Alfie, Jeong, Yeon-Tae, Bordi, Matteo, Russo, Francesco, Campello, Silvia, Gallo, Angela, Filomeni, Giuseppe, Lanzetti, Letizia, Sears, Rosalie C, Hamerlik, Petra, Bartolazzi, Armando, Hynds, Robert E, Pearce, David R, Swanton, Charle, Pagano, Michele, Velasco, Guillermo, Papaleo, Elena, De Zio, Daniela, Maya-Mendoza, Apolinar, Locatelli, Franco, Bartek, Jiri, and Cecconi, Francesco
- Subjects
0301 basic medicine ,Genome instability ,Cyclin D ,Cyclin-Dependent Kinase ,AMBRA1 ,medicine.disease_cause ,Ambra 1 ,S Phase ,Mice ,0302 clinical medicine ,Genes, Tumor Suppressor ,Synthetic Lethal Mutation ,Tissue homeostasis ,Cyclin ,Mice, Knockout ,Multidisciplinary ,Cell Cycle ,CELL CICLE ,Adaptor Proteins ,Gene Expression Regulation, Developmental ,Cell cycle ,Cyclin-Dependent Kinases ,Cell biology ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,030220 oncology & carcinogenesis ,Human ,DNA Replication ,Settore BIO/06 ,Biology ,Article ,Genomic Instability ,NO ,Cell Line ,03 medical and health sciences ,Cyclin-dependent kinase ,medicine ,Animals ,Humans ,Settore BIO/10 ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,Cell growth ,Animal ,Signal Transducing ,Genética ,Ambra 1, S Phase, Cell Cycle, Cyclin D, Genomic Instability ,030104 developmental biology ,Checkpoint Kinase 1 ,biology.protein ,AMBRA ,Synthetic Lethal Mutations ,Carcinogenesis - Abstract
Mammalian development, adult tissue homeostasis and the avoidance of severe diseases including cancer require a properly orchestrated cell cycle, as well as error-free genome maintenance. The key cell-fate decision to replicate the genome is controlled by two major signalling pathways that act in parallel—the MYC pathway and the cyclin D–cyclin-dependent kinase (CDK)–retinoblastoma protein (RB) pathway1,2. Both MYC and the cyclin D–CDK–RB axis are commonly deregulated in cancer, and this is associated with increased genomic instability. The autophagic tumour-suppressor protein AMBRA1 has been linked to the control of cell proliferation, but the underlying molecular mechanisms remain poorly understood. Here we show that AMBRA1 is an upstream master regulator of the transition from G1 to S phase and thereby prevents replication stress. Using a combination of cell and molecular approaches and in vivo models, we reveal that AMBRA1 regulates the abundance of D-type cyclins by mediating their degradation. Furthermore, by controlling the transition from G1 to S phase, AMBRA1 helps to maintain genomic integrity during DNA replication, which counteracts developmental abnormalities and tumour growth. Finally, we identify the CHK1 kinase as a potential therapeutic target in AMBRA1-deficient tumours. These results advance our understanding of the control of replication-phase entry and genomic integrity, and identify the AMBRA1–cyclin D pathway as a crucial cell-cycle-regulatory mechanism that is deeply interconnected with genomic stability in embryonic development and tumorigenesis. AMBRA1-mediated degradation of cyclin D through CRL4–DDB1 regulates cell proliferation and prevents replication stress in neurodevelopment and cancer.
- Published
- 2021
46. Redox activation of ATM enhances GSNOR translation to sustain mitophagy and tolerance to oxidative stress
- Author
-
Jonathan S. Stamler, Salvatore Rizza, Ji-Hoon Lee, Tanya T. Paull, Noemi Poerio, Giuseppina Claps, Daniela Barilà, Maria Francesca Allega, Maurizio Fraziano, Chiara Pecorari, Paola Giglio, Claudia Cirotti, Giuseppe Filomeni, Francesco Cecconi, Caroline Robert, Barbara Benassi, Cirotti, C., Rizza, S., Giglio, P., Poerio, N., Allega, M. F., Claps, G., Pecorari, C., Lee, J. -H., Benassi, B., Barila, D., Robert, C., Stamler, J. S., Cecconi, F., Fraziano, M., Paull, T. T., and Filomeni, G.
- Subjects
Senescence ,Mitochondrial ROS ,Settore BIO/06 ,Immunology ,Cell ,Context (language use) ,medicine.disease_cause ,Biochemistry ,Article ,03 medical and health sciences ,0302 clinical medicine ,Mitophagy ,Genetics ,medicine ,Molecular Biology of Disease ,Settore BIO/10 ,Molecular Biology ,Cellular Senescence ,030304 developmental biology ,0303 health sciences ,GSNOR ,Settore BIO/18 ,Chemistry ,Effector ,Autophagy ,T cell ,ROS ,Articles ,Aldehyde Oxidoreductases ,Cell biology ,Oxidative Stress ,medicine.anatomical_structure ,mitophagy ,ATM ,Autophagy & Cell Death ,Oxidation-Reduction ,030217 neurology & neurosurgery ,Oxidative stress - Abstract
The denitrosylase S‐nitrosoglutathione reductase (GSNOR) has been suggested to sustain mitochondrial removal by autophagy (mitophagy), functionally linking S‐nitrosylation to cell senescence and aging. In this study, we provide evidence that GSNOR is induced at the translational level in response to hydrogen peroxide and mitochondrial ROS. The use of selective pharmacological inhibitors and siRNA demonstrates that GSNOR induction is an event downstream of the redox‐mediated activation of ATM, which in turn phosphorylates and activates CHK2 and p53 as intermediate players of this signaling cascade. The modulation of ATM/GSNOR axis, or the expression of a redox‐insensitive ATM mutant influences cell sensitivity to nitrosative and oxidative stress, impairs mitophagy and affects cell survival. Remarkably, this interplay modulates T‐cell activation, supporting the conclusion that GSNOR is a key molecular effector of the antioxidant function of ATM and providing new clues to comprehend the pleiotropic effects of ATM in the context of immune function., Hydrogen peroxide and pro‐oxidant conditions activate ATM via oxidation of Cys2991. The resulting phospho‐signal activates CHK2 and p53 and culminates in enhanced translation of the denitrosylase GSNOR to sustain mitophagy and protect the cells against oxidative stress.
- Published
- 2021
47. Loss of Ambra1 promotes melanoma growth and invasion
- Author
-
Marco Carretta, Marco Donia, Daniel H. Madsen, Shawez Khan, Daniela De Zio, Caroline Robert, Jose Javier Bravo-Cordero, Giuseppe Filomeni, Colin J. Daniel, Maria Irene Pires Pacheco, Luca Di Leo, Valérie Bodemeyer, Thomas Sauter, Giuseppina Claps, Francesco Cecconi, Per Guldberg, Fiorella Faienza, Rosalie C. Sears, Julie Di Martino, Salvatore Rizza, Matteo Bordi, Francesca Maria Bosisio, and Alex Frias
- Subjects
0301 basic medicine ,Male ,General Physics and Astronomy ,Adaptor Proteins, Signal Transducing/genetics ,ADHESION ,Focal Adhesion Kinase 1/metabolism ,Metastasis ,Extracellular matrix ,Mice ,Multidisciplinaire, généralités & autres [F99] [Sciences du vivant] ,0302 clinical medicine ,Cell Movement ,Melanoma ,CELL MOTILITY ,Multidisciplinary ,biology ,PROLIFERATION ,PTEN Phosphohydrolase/genetics ,Adaptor Proteins ,CANCER ,Multidisciplinary Sciences ,Gene Expression Regulation, Neoplastic ,DIFFERENTIATION ,Phenotype ,030220 oncology & carcinogenesis ,Science & Technology - Other Topics ,AUTOPHAGY ,Beclin-1 ,Female ,Autophagy/physiology ,Signal Transduction ,Beclin-1/metabolism ,Proto-Oncogene Proteins B-raf ,Science ,INHIBITION ,Motility ,PTEN LOSS ,Multidisciplinary, general & others [F99] [Life sciences] ,General Biochemistry, Genetics and Molecular Biology ,Focal adhesion ,Melanoma/genetics ,03 medical and health sciences ,Cell Line, Tumor ,Proto-Oncogene Proteins B-raf/genetics ,medicine ,EXTRACELLULAR-MATRIX ,Autophagy ,PTEN ,Animals ,Humans ,Settore BIO/10 ,Settore BIO/10 - BIOCHIMICA ,neoplasms ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,Science & Technology ,FAK ,business.industry ,PTEN Phosphohydrolase ,Signal Transducing ,General Chemistry ,medicine.disease ,Autophagic Punctum ,Disease Models, Animal ,030104 developmental biology ,Focal Adhesion Kinase 1 ,Cancer research ,biology.protein ,Skin cancer ,business ,Transcriptome - Abstract
Melanoma is the deadliest skin cancer. Despite improvements in the understanding of the molecular mechanisms underlying melanoma biology and in defining new curative strategies, the therapeutic needs for this disease have not yet been fulfilled. Herein, we provide evidence that the Activating Molecule in Beclin-1-Regulated Autophagy (Ambra1) contributes to melanoma development. Indeed, we show that Ambra1 deficiency confers accelerated tumor growth and decreased overall survival in Braf/Pten-mutated mouse models of melanoma. Also, we demonstrate that Ambra1 deletion promotes melanoma aggressiveness and metastasis by increasing cell motility/invasion and activating an EMT-like process. Moreover, we show that Ambra1 deficiency in melanoma impacts extracellular matrix remodeling and induces hyperactivation of the focal adhesion kinase 1 (FAK1) signaling, whose inhibition is able to reduce cell invasion and melanoma growth. Overall, our findings identify a function for AMBRA1 as tumor suppressor in melanoma, proposing FAK1 inhibition as a therapeutic strategy for AMBRA1 low-expressing melanoma. Melanoma is the deadliest skin cancer. Despite improvements in the understanding of the molecular mechanisms underlying melanoma biology and in defining new curative strategies, the therapeutic needs for this disease have not yet been fulfilled. Herein, we provide evidence that the Activating Molecule in Beclin-1-Regulated Autophagy (Ambra1) contributes to melanoma development. Indeed, we show that Ambra1 deficiency confers accelerated tumor growth and decreased overall survival in Braf/Pten-mutated mouse models of melanoma. Also, we demonstrate that Ambra1 deletion promotes melanoma aggressiveness and metastasis by increasing cell motility/invasion and activating an EMT-like process. Moreover, we show that Ambra1 deficiency in melanoma impacts extracellular matrix remodeling and induces hyperactivation of the focal adhesion kinase 1 (FAK1) signaling, whose inhibition is able to reduce cell invasion and melanoma growth. Overall, our findings identify a function for AMBRA1 as tumor suppressor in melanoma, proposing FAK1 inhibition as a therapeutic strategy for AMBRA1 low-expressing melanoma.
- Published
- 2021
48. ATM plays antioxidant, boosting mitophagy via denitrosylation
- Author
-
Claudia Cirotti and Giuseppe Filomeni
- Subjects
DNA damage ,hydrogen peroxide ,Mitochondrion ,Biology ,medicine.disease_cause ,nitric oxide ,Mitophagy ,medicine ,oxidative stress ,Settore BIO/10 ,Molecular Biology ,chemistry.chemical_classification ,Reactive oxygen species ,GSNOR ,Autophagy ,T cell ,ADH5 ,Cell Biology ,S-Nitrosylation ,medicine.disease ,S-nitrosylation ,Cell biology ,mitophagy ,chemistry ,ATM ,Ataxia-telangiectasia ,Oxidative stress - Abstract
Mitophagy is a selective process aimed at removing damaged or burned-out mitochondria; it is activated upon different stimuli and plays a fundamental role in preventing overproduction of reactive oxygen species (ROS) that might be generated by dysfunctional mitochondria. From this angle, mitophagy can be considered a fully-fledged antioxidant process. Such a surrogate antioxidant function is recently emerging, being shared among many molecular pathways and players that are usually not included among - and, formally, do not directly act as - antioxidants. ATM (ataxia telangiectasia mutated) is a prototype of this class of "neglected" antioxidants. In spite of its well-known role in DNA damage response, many phenotypes of ataxia telangiectasia (A-T) patients are, indeed, related to chronic oxidative stress, arguing for an additional antioxidant role of ATM. In a recent study, we discovered the mechanism through which ATM exerts antioxidant activity. In particular, we provided evidence that this involves ADH5/GSNOR (alcohol dehydrogenase 5 (class III), chi polypeptide), which, in turn, sustains mitophagy via PARK2 denitrosylation, and protects the cell from detrimental effects due to ROS.
- Published
- 2020
49. ATM plays antioxidant, boosting mitophagy
- Author
-
Claudia, Cirotti and Giuseppe, Filomeni
- Subjects
Ataxia Telangiectasia ,Autophagy ,Mitophagy ,Animals ,Humans ,Ataxia Telangiectasia Mutated Proteins ,Reactive Oxygen Species ,Antioxidants ,Autophagic Punctum - Abstract
Mitophagy is a selective process aimed at removing damaged or burned-out mitochondria; it is activated upon different stimuli and plays a fundamental role in preventing overproduction of reactive oxygen species (ROS) that might be generated by dysfunctional mitochondria. From this angle, mitophagy can be considered a fully-fledged antioxidant process. Such a surrogate antioxidant function is recently emerging, being shared among many molecular pathways and players that are usually not included among – and, formally, do not directly act as – antioxidants. ATM (ataxia telangiectasia mutated) is a prototype of this class of “neglected” antioxidants. In spite of its well-known role in DNA damage response, many phenotypes of ataxia telangiectasia (A-T) patients are, indeed, related to chronic oxidative stress, arguing for an additional antioxidant role of ATM. In a recent study, we discovered the mechanism through which ATM exerts antioxidant activity. In particular, we provided evidence that this involves ADH5/GSNOR (alcohol dehydrogenase 5 (class III), chi polypeptide), which, in turn, sustains mitophagy via PARK2 denitrosylation, and protects the cell from detrimental effects due to ROS.
- Published
- 2020
50. When
- Author
-
Costanza, Montagna, Claudia, Cirotti, Salvatore, Rizza, and Giuseppe, Filomeni
- Subjects
Aging ,Muscular Diseases ,Neoplasms ,Reperfusion Injury ,Animals ,Humans ,Nitric Oxide ,Synaptic Transmission ,Mitochondria ,Signal Transduction - Published
- 2020
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.