Submitted December 20, 2007
Accepted May 22, 2008
TAT-mediated intracellular delivery of NPM-derived peptide induces apoptosis in leukemic cells and suppresses leukemogenesis in mice
Yun Zhou, Wei Du, Tara Koretsky, Grover C Bagby, and Qishen Pang*
Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
Cancer Center, Oregon Health and Sciences University, Portland, OR, United States
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
* Corresponding author; email: qishen.pang{at}cchmc.org.
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-NPM
C) and found that the fusion peptide inhibited proliferation and induced apoptotic death of primary fibroblasts and pre-leukemic stem cells. TAT-NPMC down-regulated several NF-
B-controlled survival and inflammatory proteins and suppressed NF-B-driven reporter gene activities. Using an inflammation-associated leukemia model, we demonstrate that TAT-NPMC induced proliferative suppression and apoptosis of pre-leukemic stem cells, and significantly delayed leukemic development in mice. Mechanistically, TAT-NPMC associated with wild-type NPM proteins and formed complexes with endogenous NPM and p65 at promoters of several anti-apoptotic and inflammatory genes and abrogated their transactivation by NF-B in leukemic cells. Thus, TAT-delivered NPM peptide may provide a novel therapy for inflammation-associated tumors that require NF-B signaling for survival.
