Document Detail


Targeting Survivin expression induces cell proliferation defect and subsequent cell death involving mitochondrial pathway in myeloid leukemic cells.
MedLine Citation:
PMID:  12963850     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Survivin, a member of inhibitor of apoptosis family of proteins, plays important roles in both cell proliferation and cell death. We previously observed that Survivin is overexpressed in leukemic cell lines and blasts from patients with acute myelogenous leukemia (AML). To understand the roles of Survivin in AML and search for new approaches to the treatment of AML, we inhibited Survivin expression in HL-60 cells with a Survivin anti-sense oligonucleotide (sur-AS-ODN) (ISIS 23722). This blocked significant numbers of HL-60 cells in G2/M phase, and halted cell proliferation at 24 hrs and progressing over time. There was only a slight increase in the number of apoptotic cells at 24 hrs compared with cells treated with nonsense oligonucleotide (NS-ODN). At 48 hrs, however, there were significant increases in sub-G1 phase and annexin V+ cells, suggesting that cell division defects caused cell death. This was supported by the finding that a reduction in the Survivin protein by sur-AS-ODN in cells under serum-free medium did not induce G2/M block and cell death compared to cells treated with NS-ODN. The formation of polyploid cells was observed 48 hrs after sur-AS-ODN treatment, as was the activation of caspase 3, which suggested that apoptotic cell death had occurred. The mitochondrial release of cytochrome C and Smac and the nuclear translocation of the apoptosis-inducing factor were also detected. Our results suggest that Survivin is essential for cell cycle progression in leukemic cells. Reduced Survivin expression causes a cell-cycle defect that leads to cell death through a mitochondrial pathway. This finding has potential utility for therapy of patients with AML.
Authors:
Bing Z Carter; Rui-Yu Wang; Wendy D Schober; Michele Milella; David Chism; Michael Andreeff
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  2     ISSN:  1538-4101     ISO Abbreviation:  Cell Cycle     Publication Date:    2003 Sep-Oct
Date Detail:
Created Date:  2003-09-09     Completed Date:  2004-05-11     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  488-93     Citation Subset:  IM    
Affiliation:
Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / physiology*
Cell Cycle / physiology
Cell Death / physiology*
Cell Division / physiology
DNA, Antisense / metabolism
HL-60 Cells
Humans
Microtubule-Associated Proteins / drug effects,  metabolism*
Mitochondria / metabolism
Mitochondrial Proteins
Neoplasm Proteins
Grant Support
ID/Acronym/Agency:
CA16672/CA/NCI NIH HHS; P01 CA55164/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/BIRC5 protein, human; 0/DNA, Antisense; 0/Microtubule-Associated Proteins; 0/Mitochondrial Proteins; 0/Neoplasm Proteins

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