LIVIVO - The Search Portal for Life Sciences

zur deutschen Oberfläche wechseln
Advanced search

Search results

Result 1 - 6 of total 6

Search options

  1. Article ; Online: Therapeutic opportunities for PLK1 inhibitors: Spotlight on BRCA1-deficiency and triple negative breast cancers.

    García, Iris Alejandra / Garro, Cintia / Fernandez, Elmer / Soria, Gastón

    Mutation research

    2020  Volume 821, Page(s) 111693

    Abstract: Polo-Like Kinases (PLKs) are central players of mitotic progression in Eukaryotes. Given the intimate relationship between cell cycle progression and cancer development, PLKs in general and PLK1 in particular have been thoroughly studied as biomarkers ... ...

    Abstract Polo-Like Kinases (PLKs) are central players of mitotic progression in Eukaryotes. Given the intimate relationship between cell cycle progression and cancer development, PLKs in general and PLK1 in particular have been thoroughly studied as biomarkers and potential therapeutic targets in oncology. The oncogenic properties of PLK1 overexpression across different types of human cancers are attributed to its roles in promoting mitotic entry, centrosome maturation, spindle assembly and cytokinesis. While several academic labs and pharmaceutical companies were able to develop potent and selective inhibitors of PLK1 (PLK1i) for preclinical research, such compounds have reached only limited success in clinical trials despite their great pharmacokinetics. Even though this could be attributed to multiple causes, the housekeeping roles of PLK1 in both normal and cancer cells are most likely the main reason for clinical trials failure and withdraw due to toxicities issues. Therefore, great efforts are being invested to position PLK1i in the treatment of specific types of cancers with revised dosages schemes. In this mini review we focus on two potential niches for PLK1i that are supported by recent evidence: triple negative breast cancers (TNBCs) and BRCA1-deficient cancers. On the one hand, we recollect several lines of strong evidence indicating that TNBCs are among the cancers with highest PLK1 expression and sensitivity to PLK1i. These findings are encouraging because of the limited therapeutics options available for TNBC patients, which rely mainly on classic chemotherapy. On the other hand, we discuss recent evidence that unveils synthetic lethality induction by PLK1 inhibition in BRCA1-deficient cancers cells. This previously unforeseen therapeutic link between PLK1 and BRCA1 is promising because it defines novel therapeutic opportunities for PLK1i not only for breast cancer (i.e. TNBCs with BRCA1 deficiencies), but also for other types of cancers with BRCA1-deficiencies, such as pancreatic and prostate cancers.
    MeSH term(s) Animals ; Antineoplastic Agents/therapeutic use ; BRCA1 Protein/deficiency ; Cell Cycle Proteins/antagonists & inhibitors ; Humans ; Molecular Targeted Therapy ; Protein Serine-Threonine Kinases/antagonists & inhibitors ; Proto-Oncogene Proteins/antagonists & inhibitors ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/metabolism ; Triple Negative Breast Neoplasms/pathology ; Polo-Like Kinase 1
    Chemical Substances Antineoplastic Agents ; BRCA1 Protein ; BRCA1 protein, human ; Cell Cycle Proteins ; Proto-Oncogene Proteins ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2020-02-25
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 206607-5
    ISSN 1873-135X ; 1383-5718 ; 0027-5107 ; 0165-1110 ; 0165-1161 ; 0165-7992 ; 0921-8777 ; 0165-1218 ; 1383-5726 ; 0167-8817 ; 0921-8734 ; 1383-5742
    ISSN (online) 1873-135X
    ISSN 1383-5718 ; 0027-5107 ; 0165-1110 ; 0165-1161 ; 0165-7992 ; 0921-8777 ; 0165-1218 ; 1383-5726 ; 0167-8817 ; 0921-8734 ; 1383-5742
    DOI 10.1016/j.mrfmmm.2020.111693
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 1316: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  2. Article ; Online: A novel yeast-based high-throughput method for the identification of protein palmitoylation inhibitors.

    Coronel Arrechea, Consuelo / Giolito, María Luz / García, Iris Alejandra / Soria, Gastón / Valdez Taubas, Javier

    Open biology

    2021  Volume 11, Issue 8, Page(s) 200415

    Abstract: Protein S-acylation or palmitoylation is a widespread post-translational modification that consists of the addition of a lipid molecule to cysteine residues of proteins through a thioester bond. Palmitoylation and palmitoyltransferases (PATs) have been ... ...

    Abstract Protein S-acylation or palmitoylation is a widespread post-translational modification that consists of the addition of a lipid molecule to cysteine residues of proteins through a thioester bond. Palmitoylation and palmitoyltransferases (PATs) have been linked to several types of cancers, diseases of the central nervous system and many infectious diseases where pathogens use the host cell machinery to palmitoylate their effectors. Despite the central importance of palmitoylation in cell physiology and disease, progress in the field has been hampered by the lack of potent-specific inhibitors of palmitoylation in general, and of individual PATs in particular. Herein, we present a yeast-based method for the high-throughput identification of small molecules that inhibit protein palmitoylation. The system is based on a reporter gene that responds to the acylation status of a palmitoylation substrate fused to a transcription factor. The method can be applied to heterologous PATs such as human DHHC20, mouse DHHC21 and also a PAT from the parasite
    MeSH term(s) Acyltransferases/antagonists & inhibitors ; Animals ; Giardia lamblia/drug effects ; Giardia lamblia/growth & development ; Giardia lamblia/metabolism ; High-Throughput Screening Assays ; Humans ; Lipoylation ; Mice ; Protozoan Proteins/antagonists & inhibitors ; Saccharomyces cerevisiae/drug effects ; Saccharomyces cerevisiae/growth & development ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/antagonists & inhibitors ; Small Molecule Libraries/pharmacology ; Substrate Specificity
    Chemical Substances Protozoan Proteins ; Saccharomyces cerevisiae Proteins ; Small Molecule Libraries ; Acyltransferases (EC 2.3.-) ; ZDHHC20 protein, human (EC 2.3.-) ; AKR1 protein, S cerevisiae (EC 2.3.1.-)
    Language English
    Publishing date 2021-08-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2630944-0
    ISSN 2046-2441 ; 2046-2441
    ISSN (online) 2046-2441
    ISSN 2046-2441
    DOI 10.1098/rsob.200415
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  3. Article: Persistent double strand break accumulation does not precede cell death in an Olaparib-sensitive BRCA-deficient colorectal cancer cell model.

    Paviolo, Natalia Soledad / Vega, María Belén de la / Pansa, María Florencia / García, Iris Alejandra / Calzetta, Nicolás Luis / Soria, Gastón / Gottifredi, Vanesa

    Genetics and molecular biology

    2019  Volume 43, Issue 1 suppl 1, Page(s) e20190070

    Abstract: The poly (adenosine diphosphate (ADP)-ribosyl) polymerase inhibitors (PARPi) selectively kill cancer cells with BRCA1 or BRCA2 (BRCA)-mutations. It has been proposed that cell death induction after PARPi depends on unrepaired double strand breaks (DSBs) ... ...

    Abstract The poly (adenosine diphosphate (ADP)-ribosyl) polymerase inhibitors (PARPi) selectively kill cancer cells with BRCA1 or BRCA2 (BRCA)-mutations. It has been proposed that cell death induction after PARPi depends on unrepaired double strand breaks (DSBs) that accumulate due to the homologous recombination deficiency of BRCA-mutated cells. Such accumulation of DSBs is inferred mainly from the high levels of DNA damage markers like phosphorylated histone H2AX. Herein, we developed a model of isogenic cell lines to show that depletion of BRCA causes PARPi-triggered cell death, replication stress (phosphorylated-H2AX and 53BP1 foci), and genomic instability. However, persistent DSBs accumulation was not detected under the same experimental conditions. Hence, at least in this cellular model, the trigger for cell death in PARPi-treated BRCA-depleted samples is not the accumulation of unrepaired DSBs. Instead, cell death better correlates with a rapid and aberrant resolution of DSBs by error-prone pathways that leads to severe chromosomic aberrations. Therefore, our results suggest that in PARPi-treated BRCA-deficient cells, chromosome aberrations may dually trigger both genomic instability and cell death.
    Language English
    Publishing date 2019-12-13
    Publishing country Brazil
    Document type Journal Article
    ZDB-ID 1445712-x
    ISSN 1678-4685 ; 1415-4757
    ISSN (online) 1678-4685
    ISSN 1415-4757
    DOI 10.1590/1678-4685-GMB-2019-0070
    Database MEDical Literature Analysis and Retrieval System OnLINE

    Full text online

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 3079: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  4. Article ; Online: AKT inhibition impairs PCNA ubiquitylation and triggers synthetic lethality in homologous recombination-deficient cells submitted to replication stress.

    Villafañez, Florencia / García, Iris Alejandra / Carbajosa, Sofia / Pansa, María Florencia / Mansilla, Sabrina / Llorens, María Candelaria / Angiolini, Virginia / Guantay, Laura / Jacobs, Heinz / Madauss, Kevin P / Gloger, Israel / Gottifredi, Vanesa / Bocco, Jose Luis / Soria, Gaston

    Oncogene

    2019  Volume 38, Issue 22, Page(s) 4310–4324

    Abstract: Translesion DNA synthesis (TLS) and homologous recombination (HR) cooperate during S-phase to safeguard replication forks integrity. Thus, the inhibition of TLS becomes a promising point of therapeutic intervention in HR-deficient cancers, where TLS ... ...

    Abstract Translesion DNA synthesis (TLS) and homologous recombination (HR) cooperate during S-phase to safeguard replication forks integrity. Thus, the inhibition of TLS becomes a promising point of therapeutic intervention in HR-deficient cancers, where TLS impairment might trigger synthetic lethality (SL). The main limitation to test this hypothesis is the current lack of selective pharmacological inhibitors of TLS. Herein, we developed a miniaturized screening assay to identify inhibitors of PCNA ubiquitylation, a key post-translational modification required for efficient TLS activation. After screening a library of 627 kinase inhibitors, we found that targeting the pro-survival kinase AKT leads to strong impairment of PCNA ubiquitylation. Mechanistically, we found that AKT-mediated modulation of Proliferating Cell Nuclear Antigen (PCNA) ubiquitylation after UV requires the upstream activity of DNA PKcs, without affecting PCNA ubiquitylation levels in unperturbed cells. Moreover, we confirmed that persistent AKT inhibition blocks the recruitment of TLS polymerases to sites of DNA damage and impairs DNA replication forks processivity after UV irradiation, leading to increased DNA replication stress and cell death. Remarkably, when we compared the differential survival of HR-proficient vs HR-deficient cells, we found that the combination of UV irradiation and AKT inhibition leads to robust SL induction in HR-deficient cells. We link this phenotype to AKT ability to inhibit PCNA ubiquitylation, since the targeted knockdown of PCNA E3-ligase (RAD18) and a non-ubiquitylable (PCNA K164R) knock-in model recapitulate the observed SL induction. Collectively, this work identifies AKT as a novel regulator of PCNA ubiquitylation and provides the proof-of-concept of inhibiting TLS as a therapeutic approach to selectively kill HR-deficient cells submitted to replication stress.
    MeSH term(s) Cell Death/genetics ; Cell Line ; Cell Line, Tumor ; DNA/genetics ; DNA Damage/genetics ; DNA Replication/genetics ; DNA-Directed DNA Polymerase/genetics ; HCT116 Cells ; HEK293 Cells ; Homologous Recombination/genetics ; Humans ; Proliferating Cell Nuclear Antigen/genetics ; Proto-Oncogene Proteins c-akt/genetics ; Ubiquitin-Protein Ligases/genetics ; Ubiquitination/genetics
    Chemical Substances PCNA protein, human ; Proliferating Cell Nuclear Antigen ; DNA (9007-49-2) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; DNA-Directed DNA Polymerase (EC 2.7.7.7)
    Language English
    Publishing date 2019-01-31
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639046-8
    ISSN 1476-5594 ; 0950-9232
    ISSN (online) 1476-5594
    ISSN 0950-9232
    DOI 10.1038/s41388-019-0724-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 2218: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  5. Article: PKCα Modulates Epithelial-to-Mesenchymal Transition and Invasiveness of Breast Cancer Cells Through ZEB1.

    Llorens, María Candelaria / Rossi, Fabiana Alejandra / García, Iris Alejandra / Cooke, Mariana / Abba, Martin C / Lopez-Haber, Cynthia / Barrio-Real, Laura / Vaglienti, María Victoria / Rossi, Mario / Bocco, José Luis / Kazanietz, Marcelo G / Soria, Gastón

    Frontiers in oncology

    2019  Volume 9, Page(s) 1323

    Abstract: ZEB1 is a master regulator of the Epithelial-to-Mesenchymal Transition (EMT) program. While extensive evidence confirmed the importance of ZEB1 as an EMT transcription factor that promotes tumor invasiveness and metastasis, little is known about its ... ...

    Abstract ZEB1 is a master regulator of the Epithelial-to-Mesenchymal Transition (EMT) program. While extensive evidence confirmed the importance of ZEB1 as an EMT transcription factor that promotes tumor invasiveness and metastasis, little is known about its regulation. In this work, we screened for potential regulatory links between ZEB1 and multiple cellular kinases. Exploratory
    Language English
    Publishing date 2019-11-27
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2649216-7
    ISSN 2234-943X
    ISSN 2234-943X
    DOI 10.3389/fonc.2019.01323
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  6. Article ; Online: Polo-like Kinase 1 Inhibition as a Therapeutic Approach to Selectively Target BRCA1-Deficient Cancer Cells by Synthetic Lethality Induction.

    Carbajosa, Sofía / Pansa, María Florencia / Paviolo, Natalia S / Castellaro, Andrés M / Andino, Diego L / Nigra, Ayelén D / García, Iris Alejandra / Racca, Ana C / Rodriguez-Berdini, Lucía / Angiolini, Virginia / Guantay, Laura / Villafañez, Florencia / Federico, María Belén / Rodríguez-Baili, María Celeste / Caputto, Beatriz L / Drewes, Gerard / Madauss, Kevin P / Gloger, Israel / Fernandez, Elmer /
    Gil, Germán A / Bocco, José Luis / Gottifredi, Vanesa / Soria, Gastón

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2019  Volume 25, Issue 13, Page(s) 4049–4062

    Abstract: Purpose: BRCA1 and BRCA2 deficiencies are widespread drivers of human cancers that await the development of targeted therapies. We aimed to identify novel synthetic lethal relationships with therapeutic potential using BRCA-deficient isogenic ... ...

    Abstract Purpose: BRCA1 and BRCA2 deficiencies are widespread drivers of human cancers that await the development of targeted therapies. We aimed to identify novel synthetic lethal relationships with therapeutic potential using BRCA-deficient isogenic backgrounds.
    Experimental design: We developed a phenotypic screening technology to simultaneously search for synthetic lethal (SL) interactions in BRCA1- and BRCA2-deficient contexts. For validation, we developed chimeric spheroids and a dual-tumor xenograft model that allowed the confirmation of SL induction with the concomitant evaluation of undesired cytotoxicity on BRCA-proficient cells. To extend our results using clinical data, we performed retrospective analysis on The Cancer Genome Atlas (TCGA) breast cancer database.
    Results: The screening of a kinase inhibitors library revealed that Polo-like kinase 1 (PLK1) inhibition triggers strong SL induction in BRCA1-deficient cells. Mechanistically, we found no connection between the SL induced by PLK1 inhibition and PARP inhibitors. Instead, we uncovered that BRCA1 downregulation and PLK1 inhibition lead to aberrant mitotic phenotypes with altered centrosomal duplication and cytokinesis, which severely reduced the clonogenic potential of these cells. The penetrance of PLK1/BRCA1 SL interaction was validated using several isogenic and nonisogenic cellular models, chimeric spheroids, and mice xenografts. Moreover, bioinformatic analysis revealed high-PLK1 expression in BRCA1-deficient tumors, a phenotype that was consistently recapitulated by inducing BRCA1 deficiency in multiple cell lines as well as in BRCA1-mutant cells.
    Conclusions: We uncovered an unforeseen addiction of BRCA1-deficient cancer cells to PLK1 expression, which provides a new means to exploit the therapeutic potential of PLK1 inhibitors in clinical trials, by generating stratification schemes that consider this molecular trait in patient cohorts.
    MeSH term(s) Animals ; Apoptosis/drug effects ; Apoptosis/genetics ; BRCA1 Protein/deficiency ; BRCA2 Protein/deficiency ; BRCA2 Protein/genetics ; Cell Cycle/drug effects ; Cell Cycle/genetics ; Cell Cycle Proteins/antagonists & inhibitors ; Cell Line, Tumor ; Cells, Cultured ; Chromosome Aberrations ; DNA Damage ; Disease Models, Animal ; Gene Expression ; Gene Knockdown Techniques ; Humans ; Mice ; Protein Kinase Inhibitors/pharmacology ; Protein Serine-Threonine Kinases/antagonists & inhibitors ; Proto-Oncogene Proteins/antagonists & inhibitors ; Synthetic Lethal Mutations/drug effects ; Xenograft Model Antitumor Assays ; Polo-Like Kinase 1
    Chemical Substances BRCA1 Protein ; BRCA1 protein, human ; BRCA2 Protein ; BRCA2 protein, human ; Cell Cycle Proteins ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2019-03-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-18-3516
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 4223: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

To top