Document Detail

Persistent p21Cip1 induction mediates G(1) cell cycle arrest by methylseleninic acid in DU145 prostate cancer cells.
MedLine Citation:
PMID:  20370687     Owner:  NLM     Status:  MEDLINE    
The induction of G(1) cell cycle arrest and apoptosis by second-generation selenium compounds (e.g., methylselenol precursors such as methylseleninic acid, MSeA) may contribute to their anti-cancer activities. We have documented previously induction of G(1) arrest and apoptosis by MSeA in association with upregulation of cyclin-dependent kinase inhibitor (CDKI) proteins p21Cip1 and/or p27Kip1 in DU145 prostate cancer cells. However, whether these CDKIs play a critical mediator role in G(1) arrest and apoptosis by MSeA has not been addressed. In the present work, we show exposure of p53-mutant DU145 cells to sub-apoptotic concentrations of MSeA induced p21cip1 mRNA (3 h) and protein (6 h) much faster than p27kip1 mRNA (12 h) and protein (12 h). Knocking down of p21 by siRNA completely abolished G(1) arrest induction by MSeA in DU145 cells, yet si-p27 RNA had no attenuation effect on the G(1) arrest. Depletion of p21Cip1 alone or both p21Cip1 and p27Kip1 increased MSeA-induced caspase-mediated apoptosis. Immunoprecipitation detected increased binding of p21Cip1 to CDK2 and CDK6 in MSeA-exposed DU145 cells. In DU145 xenografts from mice acutely treated with MSeA p.o., the induction of p21Cip1 was observed at 72 h of daily exposure. In p53-wild type LNCaP PCa cells and p53-null PC-3 PCa cells, MSeA modestly and transiently upregulated p21Cip1 protein level, subsiding to basal level by 24 h, without affecting P27Kip1 abundance in the same duration. Si-p21 RNA knockdown in these cells have only a partial effect to reverse G(1) arrest induction by MSeA. Together, our data support persistent, p53-independent, p21Cip1 induction as a critical mediator of MSeA-induced G(1) arrest in DU145 PCa cells, however, p21Cip1 induction and G(1) arrest were not necessary for, and may antagonize, caspase-mediated apoptosis.
Zhe Wang; Hyo-Jeong Lee; Yubo Chai; Hongbo Hu; Lei Wang; Yong Zhang; Cheng Jiang; Junxuan Lü
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Current cancer drug targets     Volume:  10     ISSN:  1873-5576     ISO Abbreviation:  Curr Cancer Drug Targets     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-10     Completed Date:  2010-08-16     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101094211     Medline TA:  Curr Cancer Drug Targets     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  307-18     Citation Subset:  IM    
The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
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MeSH Terms
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Caspases / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects*
Cyclin-Dependent Kinase Inhibitor p21 / genetics,  metabolism*
Cyclin-Dependent Kinases / metabolism
Dose-Response Relationship, Drug
G1 Phase / drug effects*
Intracellular Signaling Peptides and Proteins / metabolism
Mice, Inbred BALB C
Mice, Nude
Organoselenium Compounds / pharmacology*
Prostatic Neoplasms / drug therapy*,  genetics,  metabolism,  pathology
RNA Interference
RNA, Messenger / metabolism
Time Factors
Tumor Suppressor Protein p53 / genetics
Xenograft Model Antitumor Assays
Grant Support
Reg. No./Substance:
0/Antineoplastic Agents; 0/CDKN1A protein, human; 0/CDKN1B protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Intracellular Signaling Peptides and Proteins; 0/Organoselenium Compounds; 0/RNA, Messenger; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 28274-57-9/methylselenic acid; EC Kinases; EC 3.4.22.-/Caspases

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