A PCNA-Derived Cell Permeable Peptide Selectively Inhibits Neuroblastoma Cell Growth
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{"title"=>"A PCNA-derived cell permeable peptide selectively inhibits neuroblastoma cell growth", "type"=>"journal", "authors"=>[{"first_name"=>"Long", "last_name"=>"Gu", "scopus_author_id"=>"35752040600"}, {"first_name"=>"Shanna", "last_name"=>"Smith", "scopus_author_id"=>"56907856200"}, {"first_name"=>"Caroline", "last_name"=>"Li", "scopus_author_id"=>"15057971100"}, {"first_name"=>"Robert J.", "last_name"=>"Hickey", "scopus_author_id"=>"7101900318"}, {"first_name"=>"Jeremy M.", "last_name"=>"Stark", "scopus_author_id"=>"7403024507"}, {"first_name"=>"Gregg B.", "last_name"=>"Fields", "scopus_author_id"=>"7005777371"}, {"first_name"=>"Walter H.", "last_name"=>"Lang", "scopus_author_id"=>"55969703300"}, {"first_name"=>"John A.", "last_name"=>"Sandoval", "scopus_author_id"=>"8511383100"}, {"first_name"=>"Linda H.", "last_name"=>"Malkas", "scopus_author_id"=>"7004666030"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"372981404", "sgr"=>"84899658875", "issn"=>"19326203", "pmid"=>"24728180", "scopus"=>"2-s2.0-84899658875", "doi"=>"10.1371/journal.pone.0094773"}, "id"=>"db3f111d-8518-34d1-806a-9b833509d2f5", "abstract"=>"Proliferating cell nuclear antigen (PCNA), through its interaction with various proteins involved in DNA synthesis, cell cycle regulation, and DNA repair, plays a central role in maintaining genome stability. We previously reported a novel cancer associated PCNA isoform (dubbed caPCNA), which was significantly expressed in a broad range of cancer cells and tumor tissues, but not in non-malignant cells. We found that the caPCNA-specific antigenic site lies between L126 and Y133, a region within the interconnector domain of PCNA that is known to be a major binding site for many of PCNA's interacting proteins. We hypothesized that therapeutic agents targeting protein-protein interactions mediated through this region may confer differential toxicity to normal and malignant cells. To test this hypothesis, we designed a cell permeable peptide containing the PCNA L126-Y133 sequence. Here, we report that this peptide selectively kills human neuroblastoma cells, especially those with MYCN gene amplification, with much less toxicity to non-malignant human cells. Mechanistically, the peptide is able to block PCNA interactions in cancer cells. It interferes with DNA synthesis and homologous recombination-mediated double-stranded DNA break repair, resulting in S-phase arrest, accumulation of DNA damage, and enhanced sensitivity to cisplatin. These results demonstrate conceptually the utility of this peptide for treating neuroblastomas, particularly, the unfavorable MYCN-amplified tumors.", "link"=>"http://www.mendeley.com/research/pcnaderived-cell-permeable-peptide-selectively-inhibits-neuroblastoma-cell-growth", "reader_count"=>8, "reader_count_by_academic_status"=>{"Researcher"=>1, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>2, "Student > Master"=>2, "Professor"=>2}, "reader_count_by_user_role"=>{"Researcher"=>1, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>2, "Student > Master"=>2, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>1, "Materials Science"=>2, "Agricultural and Biological Sciences"=>2, "Chemistry"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Materials Science"=>{"Materials Science"=>2}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>2}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Unspecified"=>{"Unspecified"=>1}}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1461410"], "description"=>"<p>a) SK-N-DZ NB cells were treated in triplicates by various concentrations of 5-FAM labeled R9-caPep (gray) or R9-srbPep (dark). After cells were treated by trypsin and washed, their fluorescence intensities were determined by flow cytometry. The median fluorescence intensities for triplicate cell populations under each treatment condition were averaged and graphed plus/minus standard deviations. b) Cells treated by 10 µM 5-FAM labeled R9-caPep or R9-srbPep were examined by confocal microscopy. The nuclear areas were indicated by DAPI staining. c) Four NB cell lines with <i>MYCN</i> amplification (in black), four NB cell lines without <i>MYCN</i> amplification (in grey), human PBMCs (red cycles), and human neural crest stem cell line 7SM0032 (blue squares) were cultured in the presence of various concentrations of the R9-caPep for 72 h. Cell growth was determined by a CellTiter-Glo luminescence assay (Promega). Cells cultured in the absence of the R9-caPep were used as control. Luminescent signals in triplicates normalized to the control for each cell line were averaged and graphed plus/minus standard deviations. Black filled squares: LAN5, black triangles: SK-N-DZ, black circles: SK-N-BE(2)c, black empty squares: BE(2)c, grey diamond: SK-N-AS, grey circle: SK-N-SH, grey triangle: SK-N-MC, and grey square: SK-N-FI. d) The IC<sub>50</sub>s of the peptide on cell lines with or without MYCN amplification, determined by non-linear fit of Prism 6 (GraphPad Software, La Jolla, CA), were averaged and graphed plus/minus standard deviations. e) Total cell lysates were extracted from the indicated cell lines. The expression of MYCN and actin in these cell lines were determined by western blot.</p>", "links"=>[], "tags"=>["biotechnology", "cell biology", "Molecular cell biology", "Biochemistry", "dna", "DNA repair", "DNA replication", "Nucleic acids", "neurology", "Neurological tumors", "Clinical medicine", "pharmacology", "Drug research and development", "drug discovery", "oncology", "Cancers and neoplasms", "selective", "cytotoxicity", "r9-capep", "nb"], "article_id"=>996542, "categories"=>["Biological Sciences"], "users"=>["Long Gu", "Shanna Smith", "Caroline Li", "Robert J. Hickey", "Jeremy M. Stark", "Gregg B. Fields", "Walter H. Lang", "John A. Sandoval", "Linda H. Malkas"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0094773.g001", "stats"=>{"downloads"=>0, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Permeability_and_selective_cytotoxicity_of_R9_caPep_in_NB_cells_/996542", "title"=>"Permeability and selective cytotoxicity of R9-caPep in NB cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-11 03:17:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1461415"], "description"=>"<p>Human SK-N-BE2c NB cells were treated with or without 1 µM cisplatin for 2 h. Cells were washed twice with growth medium and were cultured in fresh medium with or without 20 µM R9-caPep for 3 weeks to allow colony formation. The colony counts in 3 dishes under each treatment condition were averaged and graphed plus/minus standard deviations.</p>", "links"=>[], "tags"=>["biotechnology", "cell biology", "Molecular cell biology", "Biochemistry", "dna", "DNA repair", "DNA replication", "Nucleic acids", "neurology", "Neurological tumors", "Clinical medicine", "pharmacology", "Drug research and development", "drug discovery", "oncology", "Cancers and neoplasms", "cisplatin"], "article_id"=>996547, "categories"=>["Biological Sciences"], "users"=>["Long Gu", "Shanna Smith", "Caroline Li", "Robert J. Hickey", "Jeremy M. Stark", "Gregg B. Fields", "Walter H. Lang", "John A. Sandoval", "Linda H. Malkas"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0094773.g005", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Enhanced_sensitivity_to_cisplatin_by_R9_caPep_/996547", "title"=>"Enhanced sensitivity to cisplatin by R9-caPep.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-11 03:17:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1461414"], "description"=>"<p>Cells pretreated with 30 µM R9-caPep or R9-srbPep for 2 h were irradiated by a ã-irradiator (5 Gy). After irradiation, cells were cultured in the presence of R9-caPep or R9-srbPep for the indicated time. a) Intracellular ãH2A.X and total H2A.X levels were determined by western blot. b) The formation of intra-nuclear ãH2A.X foci was analyzed by immunofluorescence microscopy. c) Cells containing at least 5 ãH2A.X foci were counted as ãH2A.X positive cells. The relative abundance of ãH2A.X positive cells in five randomly selected fields were averaged and graphed plus/minus standard deviation. Dark bars represent results from cells treated with the scrambled R9-srbPep; Light bars represent results from cells treated with R9-caPep. d) The DR-GFP, EJ5-GFP, and SA-GFP cell lines were transiently transfected by the pCBASce plasmid that expresses the I-SceI meganuclease. The HR, EJ, and SSA-mediated DSB repair events, indicated by the restoration of a functional GFP gene in the respective cell lines, were quantified by measuring the relative abundance of GFP-positive cells by flow cytometry. The relative abundance of GFP-positive cells in R9-caPep treated samples (light bars) were normalized to those treated with R9-srbPep (dark bars). Results from triplets for each cell line and treatment condition were averaged and graphed plus/minus standard deviations. e) Cells pretreated with R9-caPep or R9-srbPep for 2 h were ã-irradiated (5 Gy). The formation of intra-nuclear Rad51 foci was analyzed at the indicated time after ã-irradiation by immunofluorescence microscopy. f) The relative abundance of Rad51-positive cells (containing at least 5 foci) as a percent of the total number of cells in five randomly selected fields were averaged and graphed plus/minus standard deviations. The dark and gray bars represent results from cells treated by R9-srbPep or R9-caPep respectively.</p>", "links"=>[], "tags"=>["biotechnology", "cell biology", "Molecular cell biology", "Biochemistry", "dna", "DNA repair", "DNA replication", "Nucleic acids", "neurology", "Neurological tumors", "Clinical medicine", "pharmacology", "Drug research and development", "drug discovery", "oncology", "Cancers and neoplasms", "dsb"], "article_id"=>996546, "categories"=>["Biological Sciences"], "users"=>["Long Gu", "Shanna Smith", "Caroline Li", "Robert J. Hickey", "Jeremy M. Stark", "Gregg B. Fields", "Walter H. Lang", "John A. Sandoval", "Linda H. Malkas"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0094773.g004", "stats"=>{"downloads"=>1, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibition_of_DSB_repair_by_R9_caPep_/996546", "title"=>"Inhibition of DSB repair by R9-caPep.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-11 03:17:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1461416"], "description"=>"<p>a) Nude mice were randomly divided into 3 groups of 10 mice after each being injected with 5×106 SK-N-BE(2)c cells in Matrigel. Each group was treated with PBS (circle), R9-srbPep (square), or R9-caPep (triangle) by intratumoral injection. Tumor sizes were measured at the indicated time points and tumor volumes were estimated based on the length and width of the tumors (V = L×W2×0.5). The mean tumor volume for each treatment group was graphed plus/minus standard errors. ** indicates p<0.01. b) Tumor masses were measured at the end of the experiment and graphed in a scatter plot with mean plus/minus standard errors.</p>", "links"=>[], "tags"=>["biotechnology", "cell biology", "Molecular cell biology", "Biochemistry", "dna", "DNA repair", "DNA replication", "Nucleic acids", "neurology", "Neurological tumors", "Clinical medicine", "pharmacology", "Drug research and development", "drug discovery", "oncology", "Cancers and neoplasms", "r9-capep"], "article_id"=>996548, "categories"=>["Biological Sciences"], "users"=>["Long Gu", "Shanna Smith", "Caroline Li", "Robert J. Hickey", "Jeremy M. Stark", "Gregg B. Fields", "Walter H. Lang", "John A. Sandoval", "Linda H. Malkas"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0094773.g006", "stats"=>{"downloads"=>0, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibition_of_tumor_growth_by_R9_caPep_in_vivo_/996548", "title"=>"Inhibition of tumor growth by R9-caPep <i>in vivo</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-11 03:17:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1461413"], "description"=>"<p>a) SK-N-BE(2)c cells were pulsed in 10 µM of BrdU for 30 min after being pre-treated with R9-caPep or R9-srbPep for 7.5 h. The relative abundances of BrdU-positive cells in triplicates were averaged and graphed plus/minus standard deviations. b) Nuclear extracts from SK-N-BE(2)c cells were incubated with the indicated concentrations of R9-caPep (grey bars) or R9-srbPep (black bars) for 20 min. SV40 T-antigen was then added to the nuclear extracts along with premixed reaction buffer containing <sup>32</sup>P dCTP. A complete reaction mixture except for SV40 T-antigen was used as control for T-antigen-independent nucleotide incorporation. The polymerized radioactivity was measured by a scintillation counter. The T-antigen-dependent incorporation of <sup>32</sup>P dCTP was calculated by subtracting T-antigen-independent radioactivity from the total radioactivity and was normalized to the T-antigen-dependent radioactivity in PBS-treated samples. Triplicates of normalized T-antigen-dependent radioactivity for each treatment condition were averaged and graphed plus/minus standard deviations. c) SK-N-BE(2)c and non-malignant 7SM0032 cells were fixed and stained with propidium iodide (PI) after being treated with the indicated concentrations of R9-caPeptide for 48 h. The cellular PI fluorescence intensity determined by flow cytometry was analyzed by the FlowJo to model various cell populations. d) Cells grown on chamber slides were treated by R9-caPep or R9-srbPep at 40 µM for 48 h. Cells were fixed and analyzed by a TUNEL assay. Cells were imaged by a confocal microscope. TMR-red is the fluorophore that was attached to the free DNA ends. DAPI (blue) indicates the location of nuclei. The pink dots derived from the merged TMR-red and DAPI staining indicate apoptosis. e) The abundance of apoptotic cells relative to the total number of cells in six randomly selected fields were averaged and graphed plus/minus standard deviations (right). The dark and gray bars represent results from 7SM0032 and SK-N-BE(2)c cells respectively.</p>", "links"=>[], "tags"=>["biotechnology", "cell biology", "Molecular cell biology", "Biochemistry", "dna", "DNA repair", "DNA replication", "Nucleic acids", "neurology", "Neurological tumors", "Clinical medicine", "pharmacology", "Drug research and development", "drug discovery", "oncology", "Cancers and neoplasms", "replication", "induction", "s-phase", "apoptosis"], "article_id"=>996545, "categories"=>["Biological Sciences"], "users"=>["Long Gu", "Shanna Smith", "Caroline Li", "Robert J. Hickey", "Jeremy M. Stark", "Gregg B. Fields", "Walter H. Lang", "John A. Sandoval", "Linda H. Malkas"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0094773.g003", "stats"=>{"downloads"=>0, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibition_of_DNA_replication_and_induction_of_S_phase_arrest_and_apoptosis_by_R9_caPep_/996545", "title"=>"Inhibition of DNA replication and induction of S-phase arrest and apoptosis by R9-caPep.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-11 03:17:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/1461411"], "description"=>"<p>a) The real-time SPR response curves were recorded for 1000 nM recombinant PCNA (rPCNA) flowing over the PIP-box sequence of FEN1 immobilized to the surface of a CM5 chip in the presence of 0 (red), 500 (blue), or 1000 (green) nM caPep. The dose-dependent binding of rPCNA to the immobilized FEN1 PIP-box sequence were also recorded under other rPCNA concentrations ranging between 250 and 1000 nM in the presence of 0, 500, or 1000 nM caPep (response curve not shown) and were used to calculate K<sub>D</sub> of PCNA-FEN1 PIP-box interaction, as shown in the inserted table. SK-N-AS NB cells were treated with R9-caPep or R9-srbPep. Cells were fixed and immunostained with: b) mouse anti-FEN1 and goat anti-PCNA antibodies; c) mouse anti-LIGI and goat anti-PCNA antibodies; d) mouse anti-POLD3 and goat anti-PCNA antibodies. After DAPI counterstaining, nuclear co-localization of PCNA with FEN1, LIGI, or POLD3 was visualized by fluorescence confocal microscopy.</p>", "links"=>[], "tags"=>["biotechnology", "cell biology", "Molecular cell biology", "Biochemistry", "dna", "DNA repair", "DNA replication", "Nucleic acids", "neurology", "Neurological tumors", "Clinical medicine", "pharmacology", "Drug research and development", "drug discovery", "oncology", "Cancers and neoplasms", "pcna", "interactions", "capep"], "article_id"=>996543, "categories"=>["Biological Sciences"], "users"=>["Long Gu", "Shanna Smith", "Caroline Li", "Robert J. Hickey", "Jeremy M. Stark", "Gregg B. Fields", "Walter H. Lang", "John A. Sandoval", "Linda H. Malkas"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0094773.g002", "stats"=>{"downloads"=>2, "page_views"=>22, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibition_of_PCNA_interactions_by_caPep_and_R9_caPep_/996543", "title"=>"Inhibition of PCNA interactions by caPep and R9-caPep.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-04-11 03:17:05"}

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  • {"unique-ip"=>"8", "full-text"=>"30", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
  • {"unique-ip"=>"11", "full-text"=>"12", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"3", "full-text"=>"2", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
  • {"unique-ip"=>"10", "full-text"=>"9", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}

Relative Metric

{"start_date"=>"2014-01-01T00:00:00Z", "end_date"=>"2014-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences", "average_usage"=>[291]}, {"subject_area"=>"/Biology and life sciences/Biochemistry", "average_usage"=>[282]}, {"subject_area"=>"/Biology and life sciences/Genetics", "average_usage"=>[306, 482]}, {"subject_area"=>"/Medicine and health sciences/Oncology", "average_usage"=>[266]}]}
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