Document Detail

3,3'-diindolylmethane induction of p75NTR-dependent cell death via the p38 mitogen-activated protein kinase pathway in prostate cancer cells.
MedLine Citation:
PMID:  19470787     Owner:  NLM     Status:  MEDLINE    
The p75(NTR) functions as a tumor suppressor in prostate epithelial cells, where its expression declines with progression to malignant cancer. Previously, we showed that treatment with the nonsteroidal anti-inflammatory drug, indomethacin, induced p75(NTR) expression in the T24 cancer cell line leading to p75(NTR)-mediated decreased survival. Utilizing the indole moiety of indomethacin as a pharmacophore, we identified in rank-order with least efficacy, ketorolac, etodolac, indomethacin, 5-methylindole-3-acetic acid, indole-3-carbinol, and 3,3'-diindolylmethane (DIM) exhibiting greatest activity for induction of p75(NTR) levels and inhibition of cell survival. Prostate (PC-3, DU-145) and bladder (T24) cancer cells were more sensitive to DIM induction of p75(NTR)-associated loss of survival than breast (MCF7) and fibroblast (3T3) cells. Transfection of the PC-3 prostate cell line with a dominant-negative form of p75(NTR) before DIM treatment significantly rescued cell survival demonstrating a cause and effect relationship between DIM induction of p75(NTR) levels and inhibition of survival. Furthermore, siRNA knockdown of the p38 mitogen-activated protein kinase (MAPK) protein prevented induction of p75(NTR) by DIM in the PC-3 prostate cell line. DIM treatment induced phosphorylation of p38 MAPK as early as within 1 minute. Collectively, we identify DIM as an indole capable of inducing p75(NTR)-dependent apoptosis via the p38 MAPK pathway in prostate cancer cells.
Fatima S Khwaja; Shehla Wynne; Isadora Posey; Daniel Djakiew
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-05-26
Journal Detail:
Title:  Cancer prevention research (Philadelphia, Pa.)     Volume:  2     ISSN:  1940-6215     ISO Abbreviation:  Cancer Prev Res (Phila)     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2009-06-05     Completed Date:  2009-08-21     Revised Date:  2010-09-16    
Medline Journal Info:
Nlm Unique ID:  101479409     Medline TA:  Cancer Prev Res (Phila)     Country:  United States    
Other Details:
Languages:  eng     Pagination:  566-71     Citation Subset:  IM    
Department of Biochemistry, the Vincent T Lombardi Comprehensive Cancer Center, Georgetown University Medical, University of the District of Columbia, Washington, DC 20057-1436, USA.
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MeSH Terms
3T3 Cells / drug effects
Adenocarcinoma / enzymology,  pathology*
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Anticarcinogenic Agents / pharmacology*
Apoptosis / drug effects*
Breast Neoplasms / enzymology,  pathology
Cell Line, Tumor / drug effects,  enzymology
Ecdysterone / analogs & derivatives,  pharmacology
Indoles / pharmacology*
Neoplasm Proteins / physiology*
Nerve Tissue Proteins / genetics,  physiology*
Phosphorylation / drug effects
Prostatic Neoplasms / enzymology,  pathology*
Protein Processing, Post-Translational / drug effects
RNA, Small Interfering / genetics
Receptors, Nerve Growth Factor / genetics,  physiology*
Recombinant Fusion Proteins / physiology
Signal Transduction / drug effects
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors,  genetics,  physiology*
Grant Support
Reg. No./Substance:
0/Anti-Inflammatory Agents, Non-Steroidal; 0/Anticarcinogenic Agents; 0/Indoles; 0/NGFR protein, human; 0/Neoplasm Proteins; 0/Nerve Tissue Proteins; 0/RNA, Small Interfering; 0/Receptors, Nerve Growth Factor; 0/Recombinant Fusion Proteins; 13408-56-5/ponasterone A; 1968-05-4/3,3'-diindolylmethane; 5289-74-7/Ecdysterone; EC Mitogen-Activated Protein Kinases

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