Maria Monti

Professor of Biochemistry

Name Maria
Surname Monti
Institution University of Naples – Federico II
E-Mail montimar@unina.it
Address UniNa: Department of Chemical Sciences, Via Cinthia, Complesso Monte Sant’Angelo 21, 80126 Naples, Italy. Ceinge: CEINGE Biotecnologie Avanzate, Via G. Salvatore 486, 80126 Naples, Italy
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Maria Monti

Member PUBLICATIONS

  • Antineoplastic-related cardiotoxicity, morphofunctional aspects in a murine model: contribution of the new tool 2D-speckle tracking.

    Publication Date: 02/11/2016 on OncoTargets and therapy
    by Coppola C, Riccio G, Barbieri A, Monti MG, Piscopo G, Rea D, Arra C, Maurea C, De Lorenzo C, Maurea N
    DOI: 10.2147/OTT.S106528

    Considering that global left ventricular systolic radial strain is a sensitive technique for the early detection of left ventricular dysfunction due to antineoplastics and the analysis of segmental myocardial contractility, we evaluated this technique for early detection of trastuzumab-related cardiotoxicity by comparing it with cardiac structural damage.

  • Intermolecular disulfide bond influences unphosphorylated STAT3 dimerization and function.

    Publication Date: 01/10/2016 on The Biochemical journal
    by Butturini E, Gotte G, Dell'Orco D, Chiavegato G, Marino V, Canetti D, Cozzolino F, Monti M, Pucci P, Mariotto S
    DOI: 10.1042/BCJ20160294

    Signal transducer and activator of transcription 3 (STAT3) is a transcription factor activated by the phosphorylation of tyrosine 705 in response to many cytokines and growth factors. Recently, the roles for unphosphorylated STAT3 (U-STAT3) have been described in response to cytokine stimulation, in cancers, and in the maintenance of heterochromatin stability. It has been reported that U-STAT3 dimerizes, shuttles between the cytoplasm and nucleus, and binds to DNA, thereby driving genes transcription. Although many reports describe the active role of U-STAT3 in oncogenesis in addition to phosphorylated STAT3, the U-STAT3 functional pathway remains elusive.In this report, we describe the molecular mechanism of U-STAT3 dimerization, and we identify the presence of two intermolecular disulfide bridges between Cys367 and Cys542 and Cys418 and Cys426, respectively. Recently, we reported that the same cysteines contribute to the redox regulation of STAT3 signaling pathway both in vitro and in vivo The presence of these disulfides is here demonstrated to largely contribute to the structure and the stability of U-STAT3 dimer as the dimeric form rapidly dissociates upon reduction in the S-S bonds. In particular, the Cys367-Cys542 disulfide bridge is shown to be critical for U-STAT3 DNA-binding activity. Mutation of the two Cys residues completely abolishes the DNA-binding capability of U-STAT3. Spectroscopic investigations confirm that the noncovalent interactions are sufficient for proper folding and dimer formation, but that the interchain disulfide bonds are crucial to preserve the functional dimer. Finally, we propose a reaction scheme of U-STAT3 dimerization with a first common step followed by stabilization through the formation of interchain disulfide bonds.

  • Identification of p38 MAPK and JNK as new targets for correction of Wilson disease-causing ATP7B mutants.

    Publication Date: 01/06/2016 on Hepatology (Baltimore, Md.)
    by Chesi G, Hegde RN, Iacobacci S, Concilli M, Parashuraman S, Festa BP, Polishchuk EV, Di Tullio G, Carissimo A, Montefusco S, Canetti D, Monti M, Amoresano A, Pucci P, van de Sluis B, Lutsenko S, Luini A, Polishchuk RS
    DOI: 10.1002/hep.28398

    Wilson disease (WD) is an autosomal recessive disorder that is caused by the toxic accumulation of copper (Cu) in the liver. The ATP7B gene, which is mutated in WD, encodes a multitransmembrane domain adenosine triphosphatase that traffics from the trans-Golgi network to the canalicular area of hepatocytes, where it facilitates excretion of excess Cu into the bile. Several ATP7B mutations, including H1069Q and R778L that are two of the most frequent variants, result in protein products, which, although still functional, remain in the endoplasmic reticulum. Thus, they fail to reach Cu excretion sites, resulting in the toxic buildup of Cu in the liver of WD patients. Therefore, correcting the location of these mutants by leading them to the appropriate functional sites in the cell should restore Cu excretion and would be beneficial to help large cohorts of WD patients. However, molecular targets for correction of endoplasmic reticulum-retained ATP7B mutants remain elusive. Here, we show that expression of the most frequent ATP7B mutant, H1069Q, activates p38 and c-Jun N-terminal kinase signaling pathways, which favor the rapid degradation of the mutant. Suppression of these pathways with RNA interference or specific chemical inhibitors results in the substantial rescue of ATP7B(H1069Q) (as well as that of several other WD-causing mutants) from the endoplasmic reticulum to the trans-Golgi network compartment, in recovery of its Cu-dependent trafficking, and in reduction of intracellular Cu levels.

  • Strain Analysis in the Assessment of a Mouse Model of Cardiotoxicity due to Chemotherapy: Sample for Preclinical Research.

    Publication Date: 01/05/2016 on In vivo (Athens, Greece)
    by Rea D, Coppola C, Barbieri A, Monti MG, Misso G, Palma G, Bimonte S, Zarone MR, Luciano A, Liccardo D, Maiolino P, Cittadini A, Ciliberto G, Arra C, Maurea N

    In recent years, the development of more effective anticancer drugs has provided great benefits in patients' quality of life by improving both prognosis and disease-free survival. Nevertheless, the frequency and severity of side-effects, with particular reference to cardiac toxicity, have gained particular attention. The purpose of this study was to create a precise and sensitive preclinical model, able to identify early contractile dysfunction in mice treated with chemotherapy, through use of speckle-tracking echocardiography.

  • Protein conformational perturbations in hereditary amyloidosis: Differential impact of single point mutations in ApoAI amyloidogenic variants.

    Publication Date: 01/02/2016 on Biochimica et biophysica acta
    by Del Giudice R, Arciello A, Itri F, Merlino A, Monti M, Buonanno M, Penco A, Canetti D, Petruk G, Monti SM, Relini A, Pucci P, Piccoli R, Monti DM
    DOI: 10.1016/j.bbagen.2015.10.019

    Amyloidoses are devastating diseases characterized by accumulation of misfolded proteins which aggregate in fibrils. Specific gene mutations in Apolipoprotein A I (ApoAI) are associated with systemic amyloidoses. Little is known on the effect of mutations on ApoAI structure and amyloid properties. Here we performed a physico-chemical characterization of L75P- and L174S-amyloidogenic ApoAI (AApoAI) variants to shed light on the effects of two single point mutations on protein stability, proteolytic susceptibility and aggregation propensity. Both variants are destabilized in their N-terminal region and generate fibrils with different morphological features. L75P-AApoAI is significantly altered in its conformation and compactness, whereas a more flexible and pronounced aggregation-competent state is associated to L174S-AApoAI. These observations point out how single point mutations in ApoAI gene evocate differences in the physico-chemical and conformational behavior of the corresponding protein variants, with the common feature of diverting ApoAI from its natural role towards a pathogenic pathway.

  • Reversal of Warburg Effect and Reactivation of Oxidative Phosphorylation by Differential Inhibition of EGFR Signaling Pathways in Non-Small Cell Lung Cancer.

    Publication Date: 15/11/2015 on Clinical cancer research : an official journal of the American Association for Cancer Research
    by De Rosa V, Iommelli F, Monti M, Fonti R, Votta G, Stoppelli MP, Del Vecchio S
    DOI: 10.1158/1078-0432.CCR-15-0375

    One of the hallmarks of cancer cells is the excessive conversion of glucose to lactate under normoxic conditions, also known as the Warburg effect. Here, we tested whether the targeted inhibition of EGFR may revert this effect and reactivate mitochondrial oxidative phosphorylation in non-small cell lung cancer (NSCLC).

  • Doxorubicin impairs the insulin-like growth factor-1 system and causes insulin-like growth factor-1 resistance in cardiomyocytes.

    Publication Date: 08/05/2015 on PloS one
    by Fabbi P, Spallarossa P, Garibaldi S, Barisione C, Mura M, Altieri P, Rebesco B, Monti MG, Canepa M, Ghigliotti G, Brunelli C, Ameri P
    DOI: 10.1371/journal.pone.0124643

    Insulin-like growth factor-1 (IGF-1) promotes the survival of cardiomyocytes by activating type 1 IGF receptor (IGF-1R). Within the myocardium, IGF-1 action is modulated by IGF binding protein-3 (IGFBP-3), which sequesters IGF-1 away from IGF-1R. Since cardiomyocyte apoptosis is implicated in anthracycline cardiotoxicity, we investigated the effects of the anthracycline, doxorubicin, on the IGF-1 system in H9c2 cardiomyocytes.

  • Phosphorylation-regulated degradation of the tumor-suppressor form of PED by chaperone-mediated autophagy in lung cancer cells.

    Publication Date: 01/10/2014 on Journal of cellular physiology
    by Quintavalle C, Di Costanzo S, Zanca C, Tasset I, Fraldi A, Incoronato M, Mirabelli P, Monti M, Ballabio A, Pucci P, Cuervo AM, Condorelli G
    DOI: 10.1002/jcp.24569

    PED/PEA-15 is a death effector domain (DED) family member with a variety of effects on cell growth and metabolism. To get further insight into the role of PED in cancer, we aimed to find new PED interactors. Using tandem affinity purification, we identified HSC70 (Heat Shock Cognate Protein of 70 kDa)-which, among other processes, is involved in chaperone-mediated autophagy (CMA)-as a PED-interacting protein. We found that PED has two CMA-like motifs (i.e., KFERQ), one of which is located within a phosphorylation site, and demonstrate that PED is a bona fide CMA substrate and the first example in which phosphorylation modifies the ability of HSC70 to access KFERQ-like motifs and target the protein for lysosomal degradation. Phosphorylation of PED switches its function from tumor suppression to tumor promotion, and we show that HSC70 preferentially targets the unphosphorylated form of PED to CMA. Therefore, we propose that the up-regulated CMA activity characteristic of most types of cancer cell enhances oncogenesis by shifting the balance of PED function toward tumor promotion. This mechanism is consistent with the notion of a therapeutic potential for targeting CMA in cancer, as inhibition of this autophagic pathway may help restore a physiological ratio of PED forms.

  • Monitoring reversal of MET-mediated resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer using 3'-deoxy-3'-[18F]-fluorothymidine positron emission tomography.

    Publication Date: 15/09/2014 on Clinical cancer research : an official journal of the American Association for Cancer Research
    by Iommelli F, De Rosa V, Gargiulo S, Panico M, Monti M, Greco A, Gramanzini M, Ortosecco G, Fonti R, Brunetti A, Del Vecchio S
    DOI: 10.1158/1078-0432.CCR-14-0264

    MET amplification is one of the mechanisms underlying acquired resistance to EGFR tyrosine kinase inhibitors (TKI) in non-small cell lung cancer (NSCLC). Here, we tested whether 3'-deoxy-3'-[(18)F]-fluorothymidine ([(18)F]FLT) positron emission tomography/computerized tomography (PET/CT) can detect MET-mediated resistance to EGFR TKIs and monitor the effects of MET inhibitors in NSCLC.

  • S-Glutathionylation at Cys328 and Cys542 impairs STAT3 phosphorylation.

    Publication Date: 15/08/2014 on ACS chemical biology
    by Butturini E, Darra E, Chiavegato G, Cellini B, Cozzolino F, Monti M, Pucci P, Dell'Orco D, Mariotto S
    DOI: 10.1021/cb500407d

    STAT3 is a latent transcription factor that promotes cell survival and proliferation and is often constitutively active in cancers. Although many reports provide evidence that STAT3 is a direct target of oxidative stress, its redox regulation is poorly understood. Under oxidative conditions STAT3 activity can be modulated by S-glutathionylation, a reversible redox modification of cysteine residues. This suggests the possible cross-talk between phosphorylation and glutathionylation and points out that STAT3 is susceptible to redox regulation. Recently, we reported that decreasing the GSH content in different cell lines induces inhibition of STAT3 activity through the reversible oxidation of thiol groups. In the present work, we demonstrate that GSH/diamide treatment induces S-glutathionylation of STAT3 in the recombinant purified form. This effect was completely reversed by treatment with the reducing agent dithiothreitol, indicating that S-glutathionylation of STAT3 was related to formation of protein-mixed disulfides. Moreover, addition of the bulky negatively charged GSH moiety impairs JAK2-mediated STAT3 phosphorylation, very likely interfering with tyrosine accessibility and thus affecting protein structure and function. Mass mapping analysis identifies two glutathionylated cysteine residues, Cys328 and Cys542, within the DNA-binding domain and the linker domain, respectively. Site direct mutagenesis and in vitro kinase assay confirm the importance of both cysteine residues in the complex redox regulatory mechanism of STAT3. Cells expressing mutant were resistant in this regard. The data presented herein confirmed the occurrence of a redox-dependent regulation of STAT3, identified the more redox-sensitive cysteines within STAT3 structure, and may have important implications for development of new drugs.