TAT-mediated intracellular delivery of NPM-derived peptide induces apoptosis in leukemic cells and suppresses leukemogenesis in mice

Yun Zhou, Wei Du, Tara Koretsky, Graver C. Bagby, Qishen Pang

    Research output: Contribution to journalArticle

    25 Citations (Scopus)

    Abstract

    Nucleophosmin (NPM) is frequently overexpressed in leukemias and other tumors. NPM has been reported to suppress oncogene-induced senescence and apoptosis and may represent a therapeutic target for cancer. We fused a NPM-derived peptide to the HIV-TAT (TAT-NPMΔC) and found that the fusion peptide inhibited proliferation and induced apoptotic death of primary fibroblasts and preleukemic stem cells. TAT-NPM ΔC down-regulated several NF-κB-controlled survival and inflammatory proteins and suppressed NF-κB-driven reporter gene activities. Using an inflammationassociated leukemia model, we demonstrate that TAT-NPMκC induced proliferative suppression and apoptosis of preleukemic stem cells and significantly delayed leukemic development in mice. Mechanistically, TAT-NPMκC associated with wild-type NPM proteins and formed complexes with endogenous NPM and p65 at promoters of several antiapoptotic and inflammatory genes and abrogated their transactivation by NF-κB in leukemic cells. Thus, TAT-delivered NPM peptide may provide a novel therapy for inflammation-associated tumors that require NF-κB signaling for survival.

    Original languageEnglish (US)
    Pages (from-to)2474-2483
    Number of pages10
    JournalBlood
    Volume112
    Issue number6
    DOIs
    StatePublished - Sep 15 2008

    Fingerprint

    Apoptosis
    Peptides
    Stem cells
    Tumors
    Leukemia
    Stem Cells
    Genes
    Neoplasms
    Fibroblasts
    nucleophosmin
    Reporter Genes
    Oncogenes
    Transcriptional Activation
    Proteins
    Fusion reactions
    HIV
    Inflammation
    Therapeutics

    ASJC Scopus subject areas

    • Hematology
    • Biochemistry
    • Cell Biology
    • Immunology

    Cite this

    TAT-mediated intracellular delivery of NPM-derived peptide induces apoptosis in leukemic cells and suppresses leukemogenesis in mice. / Zhou, Yun; Du, Wei; Koretsky, Tara; Bagby, Graver C.; Pang, Qishen.

    In: Blood, Vol. 112, No. 6, 15.09.2008, p. 2474-2483.

    Research output: Contribution to journalArticle

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    abstract = "Nucleophosmin (NPM) is frequently overexpressed in leukemias and other tumors. NPM has been reported to suppress oncogene-induced senescence and apoptosis and may represent a therapeutic target for cancer. We fused a NPM-derived peptide to the HIV-TAT (TAT-NPMΔC) and found that the fusion peptide inhibited proliferation and induced apoptotic death of primary fibroblasts and preleukemic stem cells. TAT-NPM ΔC down-regulated several NF-κB-controlled survival and inflammatory proteins and suppressed NF-κB-driven reporter gene activities. Using an inflammationassociated leukemia model, we demonstrate that TAT-NPMκC induced proliferative suppression and apoptosis of preleukemic stem cells and significantly delayed leukemic development in mice. Mechanistically, TAT-NPMκC associated with wild-type NPM proteins and formed complexes with endogenous NPM and p65 at promoters of several antiapoptotic and inflammatory genes and abrogated their transactivation by NF-κB in leukemic cells. Thus, TAT-delivered NPM peptide may provide a novel therapy for inflammation-associated tumors that require NF-κB signaling for survival.",
    author = "Yun Zhou and Wei Du and Tara Koretsky and Bagby, {Graver C.} and Qishen Pang",
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    AU - Zhou, Yun

    AU - Du, Wei

    AU - Koretsky, Tara

    AU - Bagby, Graver C.

    AU - Pang, Qishen

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    N2 - Nucleophosmin (NPM) is frequently overexpressed in leukemias and other tumors. NPM has been reported to suppress oncogene-induced senescence and apoptosis and may represent a therapeutic target for cancer. We fused a NPM-derived peptide to the HIV-TAT (TAT-NPMΔC) and found that the fusion peptide inhibited proliferation and induced apoptotic death of primary fibroblasts and preleukemic stem cells. TAT-NPM ΔC down-regulated several NF-κB-controlled survival and inflammatory proteins and suppressed NF-κB-driven reporter gene activities. Using an inflammationassociated leukemia model, we demonstrate that TAT-NPMκC induced proliferative suppression and apoptosis of preleukemic stem cells and significantly delayed leukemic development in mice. Mechanistically, TAT-NPMκC associated with wild-type NPM proteins and formed complexes with endogenous NPM and p65 at promoters of several antiapoptotic and inflammatory genes and abrogated their transactivation by NF-κB in leukemic cells. Thus, TAT-delivered NPM peptide may provide a novel therapy for inflammation-associated tumors that require NF-κB signaling for survival.

    AB - Nucleophosmin (NPM) is frequently overexpressed in leukemias and other tumors. NPM has been reported to suppress oncogene-induced senescence and apoptosis and may represent a therapeutic target for cancer. We fused a NPM-derived peptide to the HIV-TAT (TAT-NPMΔC) and found that the fusion peptide inhibited proliferation and induced apoptotic death of primary fibroblasts and preleukemic stem cells. TAT-NPM ΔC down-regulated several NF-κB-controlled survival and inflammatory proteins and suppressed NF-κB-driven reporter gene activities. Using an inflammationassociated leukemia model, we demonstrate that TAT-NPMκC induced proliferative suppression and apoptosis of preleukemic stem cells and significantly delayed leukemic development in mice. Mechanistically, TAT-NPMκC associated with wild-type NPM proteins and formed complexes with endogenous NPM and p65 at promoters of several antiapoptotic and inflammatory genes and abrogated their transactivation by NF-κB in leukemic cells. Thus, TAT-delivered NPM peptide may provide a novel therapy for inflammation-associated tumors that require NF-κB signaling for survival.

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