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  1. Artikel ; Online: Preomic profile of BxPC-3 cells after treatment with BRC4

    Previtali, Viola / Myers, Samuel H. / Poppi, Laura / Wynne, Kieran / Casamassima, Irene / Girotto, Stefania / Di Stefano, Giuseppina / Farabegoli, Fulvia / Roberti, Marinella / Oliviero, Giorgio / Cavalli, Andrea

    Journal of Proteomics. 2023 Sept., v. 288 p.104983-

    2023  

    Abstract: BRCA2 and RAD51 are two proteins that play a central role in homologous recombination (HR) and DNA double strand break (DSB) repair. BRCA2 assists RAD51 fibrillation and defibrillation through binding with its eight BRC repeats, with BRC4 being one of ... ...

    Abstract BRCA2 and RAD51 are two proteins that play a central role in homologous recombination (HR) and DNA double strand break (DSB) repair. BRCA2 assists RAD51 fibrillation and defibrillation through binding with its eight BRC repeats, with BRC4 being one of the most efficient and best characterized. RAD51 inactivation by small molecules has been proposed as a strategy to impair BRCA2/RAD51 binding and, ultimately, the HR pathway, with the aim of making cancer cells more sensitive to PARP inhibitors (PARPi). This strategy, which mimics a synthetic lethality (SL) approach, has been successfully performed in vitro by using the myristoylated derivative of BRC4 (myr-BRC4), designed for a more efficient cell entry. The present study applies a method to obtain a proteomic fingerprint after cellular treatment with the myr-BRC4 peptide using a mass spectroscopy (MS) proteomic approach. (Data are available via ProteomeXchange with identifier PXD042696.) We performed a comparative proteomic profiling of the myr-BRC4 treated vs. untreated BxPC-3 pancreatic cancer cells and evaluated the differential expression of proteins. Among the identified proteins, we focused our attention on proteins shared by both the RAD51 and the BRCA2 interactomes, and on those whose reduction showed high statistical significance. Three downregulated proteins were identified (FANCI, FANCD2, and RPA3), and protein downregulation was confirmed through immunoblotting analysis, validating the MS approach. Our results suggest that, being a direct consequence of myr-BRC4 treatment, the detection of FANCD2, FANCI, and RPA3 downregulation could be used as an indicator for monitoring HR impairment. RAD51's inhibition has gained increasing attention because of its possible implications in personalized medicine through the SL approach. Chemical disruption of protein-protein interactions (PPIs) between RAD51 and BRCA2, or some of its partner proteins, could potentiate PARPi DNA damage-induced cell death. This could have application for difficult to treat cancers, such as BRCA-competent and olaparib (PARPi) resistant pancreatic adenocarcinoma. Despite RAD51 being a widely studied target, researchers still lack detailed mechanistic information. This has stifled progress in the field with only a few RAD51 inhibitors having been identified, none of which have gained regulatory approval. Nevertheless, the peptide BRC4 is one of the most specific and best characterized RAD51 binder and inhibitor reported to date. Our study is the first to report the proteomic fingerprint consequent to cellular treatment of myr-BRC4, to offer a reference for the discovery of specific protein/pathway alterations within DNA damage repair. Our results suggest that, being a direct consequence of myr-BRC4 treatment, and ultimately ofBRCA2/RAD51 disruption, the detection of FANCD2, FANCI, and RPA3 downregulation could be used as an indicator for monitoring DNA damage repair impairment and therefore be used to potentiate the development of new effective therapeutic strategies.
    Schlagwörter DNA ; DNA repair ; adenocarcinoma ; cell death ; death ; gene expression regulation ; homologous recombination ; immunoblotting ; mass spectrometry ; pancreatic neoplasms ; peptides ; precision medicine ; proteomics ; tumor suppressor proteins ; RAD51 ; RAD51/BRCA2 disruptors ; Synthetic lethality
    Sprache Englisch
    Erscheinungsverlauf 2023-09
    Erscheinungsort Elsevier B.V.
    Dokumenttyp Artikel ; Online
    ZDB-ID 2400835-7
    ISSN 1876-7737 ; 1874-3919
    ISSN (online) 1876-7737
    ISSN 1874-3919
    DOI 10.1016/j.jprot.2023.104983
    Datenquelle NAL Katalog (AGRICOLA)

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  2. Artikel ; Online: Preomic profile of BxPC-3 cells after treatment with BRC4.

    Previtali, Viola / Myers, Samuel H / Poppi, Laura / Wynne, Kieran / Casamassima, Irene / Girotto, Stefania / Di Stefano, Giuseppina / Farabegoli, Fulvia / Roberti, Marinella / Oliviero, Giorgio / Cavalli, Andrea

    Journal of proteomics

    2023  Band 288, Seite(n) 104983

    Abstract: BRCA2 and RAD51 are two proteins that play a central role in homologous recombination (HR) and DNA double strand break (DSB) repair. BRCA2 assists RAD51 fibrillation and defibrillation through binding with its eight BRC repeats, with BRC4 being one of ... ...

    Abstract BRCA2 and RAD51 are two proteins that play a central role in homologous recombination (HR) and DNA double strand break (DSB) repair. BRCA2 assists RAD51 fibrillation and defibrillation through binding with its eight BRC repeats, with BRC4 being one of the most efficient and best characterized. RAD51 inactivation by small molecules has been proposed as a strategy to impair BRCA2/RAD51 binding and, ultimately, the HR pathway, with the aim of making cancer cells more sensitive to PARP inhibitors (PARPi). This strategy, which mimics a synthetic lethality (SL) approach, has been successfully performed in vitro by using the myristoylated derivative of BRC4 (myr-BRC4), designed for a more efficient cell entry. The present study applies a method to obtain a proteomic fingerprint after cellular treatment with the myr-BRC4 peptide using a mass spectroscopy (MS) proteomic approach. (Data are available via ProteomeXchange with identifier PXD042696.) We performed a comparative proteomic profiling of the myr-BRC4 treated vs. untreated BxPC-3 pancreatic cancer cells and evaluated the differential expression of proteins. Among the identified proteins, we focused our attention on proteins shared by both the RAD51 and the BRCA2 interactomes, and on those whose reduction showed high statistical significance. Three downregulated proteins were identified (FANCI, FANCD2, and RPA3), and protein downregulation was confirmed through immunoblotting analysis, validating the MS approach. Our results suggest that, being a direct consequence of myr-BRC4 treatment, the detection of FANCD2, FANCI, and RPA3 downregulation could be used as an indicator for monitoring HR impairment. SIGNIFICANCE: RAD51's inhibition has gained increasing attention because of its possible implications in personalized medicine through the SL approach. Chemical disruption of protein-protein interactions (PPIs) between RAD51 and BRCA2, or some of its partner proteins, could potentiate PARPi DNA damage-induced cell death. This could have application for difficult to treat cancers, such as BRCA-competent and olaparib (PARPi) resistant pancreatic adenocarcinoma. Despite RAD51 being a widely studied target, researchers still lack detailed mechanistic information. This has stifled progress in the field with only a few RAD51 inhibitors having been identified, none of which have gained regulatory approval. Nevertheless, the peptide BRC4 is one of the most specific and best characterized RAD51 binder and inhibitor reported to date. Our study is the first to report the proteomic fingerprint consequent to cellular treatment of myr-BRC4, to offer a reference for the discovery of specific protein/pathway alterations within DNA damage repair. Our results suggest that, being a direct consequence of myr-BRC4 treatment, and ultimately ofBRCA2/RAD51 disruption, the detection of FANCD2, FANCI, and RPA3 downregulation could be used as an indicator for monitoring DNA damage repair impairment and therefore be used to potentiate the development of new effective therapeutic strategies.
    Mesh-Begriff(e) Humans ; Rad51 Recombinase/chemistry ; Rad51 Recombinase/genetics ; Rad51 Recombinase/metabolism ; Pancreatic Neoplasms/drug therapy ; Adenocarcinoma ; Proteomics ; Peptides/metabolism ; Pancreatic Neoplasms
    Chemische Substanzen Rad51 Recombinase (EC 2.7.7.-) ; Peptides
    Sprache Englisch
    Erscheinungsdatum 2023-08-01
    Erscheinungsland Netherlands
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2400835-7
    ISSN 1876-7737 ; 1874-3919
    ISSN (online) 1876-7737
    ISSN 1874-3919
    DOI 10.1016/j.jprot.2023.104983
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: New 4-Aminoproline-Based Small Molecule Cyclopeptidomimetics as Potential Modulators of α

    Sartori, Andrea / Bugatti, Kelly / Portioli, Elisabetta / Baiula, Monica / Casamassima, Irene / Bruno, Agostino / Bianchini, Francesca / Curti, Claudio / Zanardi, Franca / Battistini, Lucia

    Molecules (Basel, Switzerland)

    2021  Band 26, Heft 19

    Abstract: ... Integrin ... ...

    Abstract Integrin α
    Mesh-Begriff(e) Cell Adhesion/drug effects ; Humans ; Integrin alpha4beta1/antagonists & inhibitors ; Integrin alpha4beta1/chemistry ; Jurkat Cells ; Ligands ; Models, Molecular ; Oligopeptides/chemistry ; Oligopeptides/pharmacology ; Peptides, Cyclic/chemistry ; Peptides, Cyclic/pharmacology ; Peptidomimetics/chemistry ; Peptidomimetics/pharmacology ; Proline/analogs & derivatives ; Proline/chemistry ; Proline/pharmacology ; Protein Binding ; Protein Conformation
    Chemische Substanzen Integrin alpha4beta1 ; Ligands ; Oligopeptides ; Peptides, Cyclic ; Peptidomimetics ; aminoproline ; leucyl-aspartyl-valine (125850-12-6) ; Proline (9DLQ4CIU6V)
    Sprache Englisch
    Erscheinungsdatum 2021-10-07
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules26196066
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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