| 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 |
Abstract/OtherAbstract:
|
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. |
Authors:
|
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 |
Related Documents
:
|
6260157 - The activities of thymidine metabolising enzymes during the cell cycle of a human lymph... 3125857 - Cell cycle regulation of poly(adp-ribose) synthetase in fr3t3 cells. 22752387 - Attenuation of aβ-induced neurotoxicity by thymoquinone via inhibition of mitochondrial... 15184397 - Cell cycle progression after cleavage failure: mammalian somatic cells do not possess a... 16303617 - Phytoestrogen metabolites are much more active than phytoestrogens themselves in increa... 16077937 - Mechanism of telomerase repression during terminal differentiation of normal epithelial... |
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 |
Affiliation:
|
Cancer Research Center of Hawaii, University of Hawaii at Manoa, 1236 Lauhala Street, Honolulu, HI 96813, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
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 Humans 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 | |
ID/Acronym/Agency:
|
R01CA18138/CA/NCI NIH HHS; R01CA79909/CA/NCI NIH HHS |
| Chemical | |
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 4.1.1.17/Ornithine Decarboxylase; EC 4.1.1.50/Adenosylmethionine Decarboxylase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Activation of NF-kappaB following detachment delays apoptosis in intestinal epithelial cells.
Next Document: Estrogen receptors alfa (ERalpha) and beta (ERbeta) differentially regulate proliferation and apopto...