Document Detail

Key role for p27Kip1, retinoblastoma protein Rb, and MYCN in polyamine inhibitor-induced G1 cell cycle arrest in MYCN-amplified human neuroblastoma cells.
MedLine Citation:
PMID:  16007177     Owner:  NLM     Status:  MEDLINE    
Alpha-difluoromethylornithine (DFMO) inhibits the proto-oncogene ornithine decarboxylase (ODC) and is known to induce cell cycle arrest. However, the effect of DFMO on human neuroblastoma (NB) cells and the exact mechanism of DFMO-induced cell death are largely unknown. Treatment with DFMO in combination with SAM486A, an S-adenosylmethionine decarboxylase (AdoMetDC) inhibitor, has been shown to enhance polyamine pool depletion. Therefore, we analysed the mechanism of action of DFMO and/or SAM486A in two established MYCN-amplified human NB cell lines. DFMO and SAM486A caused rapid cell growth inhibition, polyamine depletion, and G1 cell cycle arrest without apoptosis in cell lines LAN-1 and NMB-7. These effects were enhanced with combined inhibitors and largely prevented by cotreatment with exogenous polyamines. The G1 cell cycle arrest was concomitant with an increase in cyclin-dependent kinase inhibitor p27Kip1. In a similar fashion, DFMO and DFMO/SAM486A inhibited the phosphorylation of the G1/S transition-regulating retinoblastoma protein Rb at residues Ser795 and Ser807/811. Moreover, we observed a dramatic decrease in MYCN protein levels. Overexpression of MYCN induces an aggressive NB phenotype with malignant behavior. We show for the first time that DFMO and SAM486A induce G1 cell cycle arrest in NB cells through p27Kip1 and Rb hypophosphorylation.
Christopher J Wallick; Ivonne Gamper; Mike Thorne; David J Feith; Kelsie Y Takasaki; Shannon M Wilson; Jennifer A Seki; Anthony E Pegg; Craig V Byus; André S Bachmann
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Oncogene     Volume:  24     ISSN:  0950-9232     ISO Abbreviation:  Oncogene     Publication Date:  2005 Aug 
Date Detail:
Created Date:  2005-08-25     Completed Date:  2005-09-14     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  5606-18     Citation Subset:  IM    
Cancer Research Center of Hawaii, University of Hawaii at Manoa, 1236 Lauhala Street, Honolulu, HI 96813, USA.
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MeSH Terms
Adenosylmethionine Decarboxylase / antagonists & inhibitors,  metabolism
Amidines / pharmacology
Cell Cycle Proteins / metabolism*
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclin-Dependent Kinase Inhibitor p27
Enzyme Inhibitors / pharmacology
G1 Phase / drug effects*
Gene Expression Regulation, Neoplastic
Indans / pharmacology
Neuroblastoma / genetics,  metabolism*,  pathology
Nuclear Proteins / genetics*,  metabolism*
Oncogene Proteins / genetics*,  metabolism*
Ornithine Decarboxylase / metabolism
Polyamines / antagonists & inhibitors*,  metabolism
Retinoblastoma Protein / metabolism*
Tumor Suppressor Proteins / metabolism*
Grant Support
Reg. No./Substance:
0/Amidines; 0/Cell Cycle Proteins; 0/Enzyme Inhibitors; 0/Indans; 0/MYCN protein, human; 0/Nuclear Proteins; 0/Oncogene Proteins; 0/Polyamines; 0/Retinoblastoma Protein; 0/Tumor Suppressor Proteins; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 149400-88-4/4-amidinoindan-1-one 2'-amidinohydrazone; EC Decarboxylase; EC Decarboxylase

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