10 results on '"G. Laudiero"'
Search Results
2. Functional characterization of TRAP1 pathway in multidrug resistance in human colorectal carcinoma
- Author
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M. Landriscina, F. Maddalena, E. Costantino, A. Piscazzi, A. Fersini, G. Laudiero, AMOROSO, MARIA ROSARIA, ESPOSITO, FRANCA, M., Landriscina, F., Maddalena, E., Costantino, A., Piscazzi, A., Fersini, G., Laudiero, Amoroso, MARIA ROSARIA, and Esposito, Franca
- Published
- 2009
3. PP21 LACTOBACILLUS RHAMNOSUS GG (LGG) INDUCES ENTEROCYTE PROLIFERATION AND DIFFERENTIATION THROUGH THE ACTIVATION OF MAP KINASES, PI3K/AKT AND GLUTATHIONE (GSH) SIGNALLING
- Author
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G. Laudiero, C. Armellino, Vittoria Buccigrossi, G. Polito, Eliana Ruberto, F. Pepe, R. Merone, Alfredo Guarino, and Eugenia Bruzzese
- Subjects
Hepatology ,biology ,business.industry ,Kinase ,Enterocyte ,Gastroenterology ,Glutathione ,biology.organism_classification ,Molecular biology ,chemistry.chemical_compound ,Signalling ,medicine.anatomical_structure ,chemistry ,Lactobacillus rhamnosus ,Medicine ,business ,Protein kinase B ,PI3K/AKT/mTOR pathway - Published
- 2010
4. Chloride secretion induced by rotavirus is oxidative stress-dependent and inhibited by Saccharomyces boulardii in human enterocytes.
- Author
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Buccigrossi V, Laudiero G, Russo C, Miele E, Sofia M, Monini M, Ruggeri FM, and Guarino A
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- Acetylcysteine metabolism, Antioxidants metabolism, Caco-2 Cells, Cell Line, Tumor, Enterocytes microbiology, Enterocytes virology, Glutathione metabolism, Glycoproteins metabolism, Humans, Intestinal Mucosa metabolism, Intestines microbiology, Intestines virology, Reactive Oxygen Species metabolism, Rotavirus Infections metabolism, Rotavirus Infections virology, Toxins, Biological metabolism, Viral Nonstructural Proteins metabolism, Chlorides metabolism, Enterocytes metabolism, Oxidative Stress physiology, Rotavirus metabolism, Rotavirus Infections microbiology, Saccharomyces metabolism
- Abstract
Rotavirus (RV) infection causes watery diarrhea via multiple mechanisms, primarily chloride secretion in intestinal epithelial cell. The chloride secretion largely depends on non-structural protein 4 (NSP4) enterotoxic activity in human enterocytes through mechanisms that have not been defined. Redox imbalance is a common event in cells infected by viruses, but the role of oxidative stress in RV infection is unknown. RV SA11 induced chloride secretion in association with an increase in reactive oxygen species (ROS) in Caco-2 cells. The ratio between reduced (GSH) and oxidized (GSSG) glutathione was decreased by RV. The same effects were observed when purified NSP4 was added to Caco-2 cells. N-acetylcysteine (NAC), a potent antioxidant, strongly inhibited the increase in ROS and GSH imbalance. These results suggest a link between oxidative stress and RV-induced diarrhea. Because Saccharomyces boulardii (Sb) has been effectively used to treat RV diarrhea, we tested its effects on RV-infected cells. Sb supernatant prevented RV-induced oxidative stress and strongly inhibited chloride secretion in Caco-2 cells. These results were confirmed in an organ culture model using human intestinal biopsies, demonstrating that chloride secretion induced by RV-NSP4 is oxidative stress-dependent and is inhibited by Sb, which produces soluble metabolites that prevent oxidative stress. The results of this study provide novel insights into RV-induced diarrhea and the efficacy of probiotics.
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- 2014
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5. The mitochondrial chaperone TRAP1 promotes neoplastic growth by inhibiting succinate dehydrogenase.
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Sciacovelli M, Guzzo G, Morello V, Frezza C, Zheng L, Nannini N, Calabrese F, Laudiero G, Esposito F, Landriscina M, Defilippi P, Bernardi P, and Rasola A
- Subjects
- Carcinogenesis metabolism, Cell Line, Tumor, Cell Proliferation, HeLa Cells, Humans, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Mitochondria metabolism, Oxygen Consumption, RNA Interference, RNA, Small Interfering, HSP90 Heat-Shock Proteins metabolism, Neoplasms metabolism, Succinate Dehydrogenase antagonists & inhibitors
- Abstract
We report that the mitochondrial chaperone TRAP1, which is induced in most tumor types, is required for neoplastic growth and confers transforming potential to noncancerous cells. TRAP1 binds to and inhibits succinate dehydrogenase (SDH), the complex II of the respiratory chain. The respiratory downregulation elicited by TRAP1 interaction with SDH promotes tumorigenesis by priming the succinate-dependent stabilization of the proneoplastic transcription factor HIF1α independently of hypoxic conditions. These findings provide a mechanistic clue to explain the switch to aerobic glycolysis of tumors and identify TRAP1 as a promising antineoplastic target., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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6. TRAP1 and the proteasome regulatory particle TBP7/Rpt3 interact in the endoplasmic reticulum and control cellular ubiquitination of specific mitochondrial proteins.
- Author
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Amoroso MR, Matassa DS, Laudiero G, Egorova AV, Polishchuk RS, Maddalena F, Piscazzi A, Paladino S, Sarnataro D, Garbi C, Landriscina M, and Esposito F
- Subjects
- ATPases Associated with Diverse Cellular Activities, Cell Line, Tumor, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Endoplasmic Reticulum genetics, Endoplasmic Reticulum pathology, Endoplasmic Reticulum Chaperone BiP, Gene Silencing, HSP90 Heat-Shock Proteins genetics, Humans, Mitochondrial Proteins genetics, Neoplasm Proteins genetics, Proteasome Endopeptidase Complex genetics, Protein Folding, Colorectal Neoplasms metabolism, Endoplasmic Reticulum metabolism, Endoplasmic Reticulum Stress, HSP90 Heat-Shock Proteins metabolism, Mitochondrial Proteins metabolism, Neoplasm Proteins metabolism, Proteasome Endopeptidase Complex metabolism, Ubiquitination
- Abstract
Tumor necrosis factor receptor-associated protein-1 (TRAP1) is a mitochondrial (MITO) antiapoptotic heat-shock protein. The information available on the TRAP1 pathway describes just a few well-characterized functions of this protein in mitochondria. However, our group's use of mass-spectrometric analysis identified TBP7, an AAA-ATPase of the 19S proteasomal subunit, as a putative TRAP1-interacting protein. Surprisingly, TRAP1 and TBP7 colocalize in the endoplasmic reticulum (ER), as demonstrated by biochemical and confocal/electron microscopic analyses, and interact directly, as confirmed by fluorescence resonance energy transfer analysis. This is the first demonstration of TRAP1's presence in this cellular compartment. TRAP1 silencing by short-hairpin RNAs, in cells exposed to thapsigargin-induced ER stress, correlates with upregulation of BiP/Grp78, thus suggesting a role of TRAP1 in the refolding of damaged proteins and in ER stress protection. Consistently, TRAP1 and/or TBP7 interference enhanced stress-induced cell death and increased intracellular protein ubiquitination. These experiments led us to hypothesize an involvement of TRAP1 in protein quality control for mistargeted/misfolded mitochondria-destined proteins, through interaction with the regulatory proteasome protein TBP7. Remarkably, expression of specific MITO proteins decreased upon TRAP1 interference as a consequence of increased ubiquitination. The proposed TRAP1 network has an impact in vivo, as it is conserved in human colorectal cancers, is controlled by ER-localized TRAP1 interacting with TBP7 and provides a novel model of the ER-mitochondria crosstalk.
- Published
- 2012
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7. Sorcin induces a drug-resistant phenotype in human colorectal cancer by modulating Ca(2+) homeostasis.
- Author
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Maddalena F, Laudiero G, Piscazzi A, Secondo A, Scorziello A, Lombardi V, Matassa DS, Fersini A, Neri V, Esposito F, and Landriscina M
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- Antineoplastic Agents pharmacology, Apoptosis drug effects, Calcium-Binding Proteins chemistry, Calcium-Binding Proteins metabolism, Caspase 12 metabolism, Caspase 3 metabolism, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Drug Resistance, Multiple genetics, Endoplasmic Reticulum Chaperone BiP, Endoplasmic Reticulum Stress drug effects, Gene Expression Regulation, Neoplastic, HCT116 Cells, HT29 Cells, Humans, Immunoblotting, Membrane Potential, Mitochondrial drug effects, Molecular Weight, Protein Isoforms chemistry, Protein Isoforms genetics, Protein Isoforms metabolism, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Up-Regulation, Calcium metabolism, Calcium-Binding Proteins genetics, Colorectal Neoplasms genetics, Drug Resistance, Neoplasm genetics, Homeostasis
- Abstract
The Ca(2+)-binding protein sorcin regulates intracellular calcium homeostasis and plays a role in the induction of drug resistance in human cancers. Recently, an 18 kDa mitochondrial isoform of sorcin was reported to participate in antiapoptosis in human colorectal cancer (CRC), but information remains lacking about the functional role of the more abundant 22 kDa isoform of sorcin expressed in CRC. We found the 22 kDa isoform to be widely expressed in human CRC cells, whether or not they were drug resistant. Its upregulation in drug-sensitive cells induced resistance to 5-fluorouracil, oxaliplatin, and irinotecan, whereas its downregulation sensitized CRC cells to these chemotherapeutic agents. Sorcin enhances the accumulation of Ca(2+) in the endoplasmic reticulum (ER), preventing ER stress, and, in support of this function, we found that the 22 kDa isoform of sorcin was upregulated under conditions of ER stress. In contrast, RNAi-mediated silencing of sorcin activated caspase-3, caspase-12, and GRP78/BiP, triggering apoptosis through the mitochondrial pathway. Our findings establish that CRC cells overexpress sorcin as an adaptive mechanism to prevent ER stress and escape apoptosis triggered by chemotherapeutic agents, prompting its further investigation as a novel molecular target to overcome MDR.
- Published
- 2011
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8. The HIV-1 transactivator factor (Tat) induces enterocyte apoptosis through a redox-mediated mechanism.
- Author
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Buccigrossi V, Laudiero G, Nicastro E, Miele E, Esposito F, and Guarino A
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- Acetylcysteine pharmacology, Cell Line, Humans, Oxidation-Reduction, Oxidative Stress, Reactive Oxygen Species metabolism, Apoptosis, Enterocytes cytology, Gene Products, tat physiology, HIV-1 physiology
- Abstract
The intestinal mucosa is an important target of human immunodeficiency virus (HIV) infection. HIV virus induces CD4+ T cell loss and epithelial damage which results in increased intestinal permeability. The mechanisms involved in nutrient malabsorption and alterations of intestinal mucosal architecture are unknown. We previously demonstrated that HIV-1 transactivator factor (Tat) induces an enterotoxic effect on intestinal epithelial cells that could be responsible for HIV-associated diarrhea. Since oxidative stress is implicated in the pathogenesis and morbidity of HIV infection, we evaluated whether Tat induces apoptosis of human enterocytes through oxidative stress, and whether the antioxidant N-acetylcysteine (NAC) could prevent it. Caco-2 and HT29 cells or human intestinal mucosa specimens were exposed to Tat alone or combined with NAC. In an in-vitro cell model, Tat increased the generation of reactive oxygen species and decreased antioxidant defenses as judged by a reduction in catalase activity and a reduced (GSH)/oxidized (GSSG) glutathione ratio. Tat also induced cytochrome c release from mitochondria to cytosol, and caspase-3 activation. Rectal dialysis samples from HIV-infected patients were positive for the oxidative stress marker 8-hydroxy-2'-deoxyguanosine. GSH/GSSG imbalance and apoptosis occurred in jejunal specimens from HIV-positive patients at baseline and from HIV-negative specimens exposed to Tat. Experiments with neutralizing anti-Tat antibodies showed that these effects were direct and specific. Pre-treatment with NAC prevented Tat-induced apoptosis and restored the glutathione balance in both the in-vitro and the ex-vivo model. These findings indicate that oxidative stress is one of the mechanism involved in HIV-intestinal disease., (© 2011 Buccigrossi et al.)
- Published
- 2011
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- View/download PDF
9. Mitochondrial chaperone Trap1 and the calcium binding protein Sorcin interact and protect cells against apoptosis induced by antiblastic agents.
- Author
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Landriscina M, Laudiero G, Maddalena F, Amoroso MR, Piscazzi A, Cozzolino F, Monti M, Garbi C, Fersini A, Pucci P, and Esposito F
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- Bone Neoplasms metabolism, Bone Neoplasms pathology, Calcium metabolism, Cell Line, Tumor, Colonic Neoplasms pathology, Drug Resistance, Neoplasm, HCT116 Cells, Humans, Osteosarcoma metabolism, Osteosarcoma pathology, Protein Structure, Tertiary, Substrate Specificity, Apoptosis physiology, Calcium-Binding Proteins metabolism, Colonic Neoplasms metabolism, HSP90 Heat-Shock Proteins metabolism, Mitochondria metabolism
- Abstract
TRAP1, a mitochondrial chaperone (Hsp75) with antioxidant and antiapoptotic functions, is involved in multidrug resistance in human colorectal carcinoma cells. Through a proteomic analysis of TRAP1 coimmunoprecipitation complexes, the Ca(2+)-binding protein Sorcin was identified as a new TRAP1 interactor. This result prompted us to investigate the presence and role of Sorcin in mitochondria from human colon carcinoma cells. Using fluorescence microscopy and Western blot analysis of purified mitochondria and submitochondrial fractions, we showed the mitochondrial localization of an isoform of Sorcin with an electrophoretic motility lower than 20 kDa that specifically interacts with TRAP1. Furthermore, the effects of overexpressing or downregulating Sorcin and/or TRAP1 allowed us to demonstrate a reciprocal regulation between these two proteins and to show that their interaction is required for Sorcin mitochondrial localization and TRAP1 stability. Indeed, the depletion of TRAP1 by short hairpin RNA in colorectal carcinoma cells lowered Sorcin levels in mitochondria, whereas the depletion of Sorcin by small interfering RNA increased TRAP1 degradation. We also report several lines of evidence suggesting that intramitochondrial Sorcin plays a role in TRAP1 cytoprotection. Finally, preliminary evidence that TRAP1 and Sorcin are both implicated in multidrug resistance and are coupregulated in human colorectal carcinomas is provided. These novel findings highlight a new role for Sorcin, suggesting that some of its previously reported cytoprotective functions may be explained by involvement in mitochondrial metabolism through the TRAP1 pathway., ((c)2010 AACR.)
- Published
- 2010
- Full Text
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10. Adaptation to oxidative stress, chemoresistance, and cell survival.
- Author
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Landriscina M, Maddalena F, Laudiero G, and Esposito F
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- Animals, Cell Survival genetics, Cell Survival physiology, Drug Resistance, Neoplasm genetics, Gene Expression Regulation, Neoplastic genetics, Gene Expression Regulation, Neoplastic physiology, Humans, Mitochondria metabolism, Mitochondria physiology, Models, Biological, Neoplasms genetics, Neoplasms metabolism, Oxidative Stress genetics, Reactive Oxygen Species metabolism, Signal Transduction genetics, Signal Transduction physiology, Adaptation, Physiological physiology, Drug Resistance, Neoplasm physiology, Neoplasms pathology, Oxidative Stress physiology
- Abstract
The discovery of some additional properties and functions of reactive oxygen species (ROS), beyond their toxic effects, provides a novel scenario for the molecular basis and cell regulation of several pathophysiologic processes. ROS are generated by redox-sensitive, prosurvival signaling pathways and function as second messengers in the transduction of several extracellular signals. A complex intracellular redox buffering network has developed to adapt and protect cells against the dangerous effects of oxidative stress. However, pathways involved in ROS-adaptive response may also play a critical role in protecting cells against cytotoxic effects of anticancer agents, thus supporting the hypothesis of a correlation between adaptation/resistance to oxidative stress and resistance to anticancer drugs. This review summarizes the main systems involved in the adaptive responses: an overview on the pathophysiologic relevance of mitochondria on redox-sensitive transcription factors and genes and main antioxidant networks in tumor cells is provided. One of the major aims is to highlight the adaptive mechanisms and their interplay in the intricate connection between oncogenic signaling, oxidative stress, and chemoresistance. Clarification of these mechanisms has tremendous application potential, in terms of developing novel molecular-targeted anticancer therapies and innovative strategies for rational combination of these agents with chemotherapeutic or tumor-specific biologic drugs.
- Published
- 2009
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