TAT-mediated intracellular delivery of NPM-derived peptide induces apoptosis in leukemic cells and suppresses leukemogenesis in mice.
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-NPMDeltaC) and found that the fusion peptide inhibited proliferation and induced apoptotic death of primary fibroblasts and preleukemic stem cells. TAT-NPMDeltaC down-regulated several NF-kappaB-controlled survival and inflammatory proteins and suppressed NF-kappaB-driven reporter gene activities. Using an inflammation-associated leukemia model, we demonstrate that TAT-NPMDeltaC induced proliferative suppression and apoptosis of preleukemic stem cells and significantly delayed leukemic development in mice. Mechanistically, TAT-NPMDeltaC 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-kappaB in leu-kemic cells. Thus, TAT-delivered NPM peptide may provide a novel therapy for inflammation-associated tumors that require NF-kappaB signaling for survival.
Zhou
Yun
Y
Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, OH 45229, USA.
Du
Wei
W
Koretsky
Tara
T
Bagby
Grover C
GC
Pang
Qishen
Q
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D015696:Gene Products, tat / Q000627:therapeutic use*; D007249:Inflammation; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D014411:Neoplastic Stem Cells / Q000473:pathology; D009687:Nuclear Proteins / Q000008:administration & dosage*; D000090243:Nucleophosmin; D010446:Peptide Fragments / Q000008:administration & dosage*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000627:therapeutic use
D015696:Gene Products, tat; D016328:NF-kappa B; D009687:Nuclear Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D000090243:Nucleophosmin