Document Detail


3,3'-Diindolylmethane induces a G(1) arrest in human prostate cancer cells irrespective of androgen receptor and p53 status.
MedLine Citation:
PMID:  19433067     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
3,3'-Diindolylmethane (DIM) is a potential chemopreventive phytochemical derived from Brassica vegetables. In this study we characterized the effect of DIM on cell cycle regulation in both androgen-dependent LNCaP and androgen receptor negative p53 mutant DU145 human prostate cancer cells. DIM had an anti-proliferative effect on both LNCaP and DU145 cells, as it significantly inhibited [3H]-thymidine incorporation. FACS analysis revealed a DIM-mediated G(1) cell cycle arrest. DIM strongly inhibited the expression of cdk2 and cdk4 protein and increased the expression of the cell cycle inhibitor p27(Kip1) protein in LNCaP and DU145 cells. Promoter deletion studies with p27(Kip1) reporter gene constructs showed that this DIM-mediated increase in p27(Kip1) was dependent on the Sp1 transcription factor. Moreover, using a dominant negative inhibitor of p38 MAPK, we showed that the induction of p27(Kip1) and subsequent G(1) arrest by DIM involve activation of the p38 MAPK pathway in the DU145 cells. Taken together, our results indicate that DIM is able to stop the cell cycle progression of human prostate cancer cells regardless of their androgen-dependence and p53 status, by differentially modulating cell cycle regulatory pathways. The Sp1 and p38 MAPK pathways mediate the DIM cell cycle regulatory effect in DU145 cells.
Authors:
Omar I Vivar; Chia-Lei Lin; Gary L Firestone; Leonard F Bjeldanes
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-05-09
Journal Detail:
Title:  Biochemical pharmacology     Volume:  78     ISSN:  1873-2968     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-07-07     Completed Date:  2009-07-14     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  469-76     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Base Sequence
Blotting, Western
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclin-Dependent Kinase Inhibitor p27 / biosynthesis
Cyclin-Dependent Kinases / antagonists & inhibitors
DNA Primers
Flow Cytometry
G1 Phase / drug effects*
Humans
Indoles / pharmacology*
Male
Prostatic Neoplasms / genetics,  metabolism,  pathology*
Receptors, Androgen / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Tumor Suppressor Protein p53 / metabolism*
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors,  metabolism
Grant Support
ID/Acronym/Agency:
CA102360/CA/NCI NIH HHS; CA69056/CA/NCI NIH HHS; R01 CA069056-04/CA/NCI NIH HHS; R01 CA069056-05/CA/NCI NIH HHS; R01 CA069056-06/CA/NCI NIH HHS; R01 CA069056-08/CA/NCI NIH HHS; R01 CA069056-09/CA/NCI NIH HHS; R01 CA102360/CA/NCI NIH HHS; R01 CA102360-01A1/CA/NCI NIH HHS; R01 CA102360-02/CA/NCI NIH HHS; R01 CA102360-03/CA/NCI NIH HHS; R01 CA102360-04/CA/NCI NIH HHS; R01 CA102360-05/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/DNA Primers; 0/Indoles; 0/Receptors, Androgen; 0/Tumor Suppressor Protein p53; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; EC 2.7.11.22/Cyclin-Dependent Kinases; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; SSZ9HQT61Z/3,3'-diindolylmethane
Comments/Corrections

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