3,3'-diindolylmethane induction of p75NTR-dependent cell death via the p38 mitogen-activated protein kinase pathway in prostate cancer cells.
Cancer Prev Res (Phila)
; 2(6): 566-71, 2009 Jun.
Article
em En
| MEDLINE
| ID: mdl-19470787
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
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Adenocarcinoma
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Anticarcinógenos
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Receptores de Fator de Crescimento Neural
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Apoptose
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Proteínas Quinases p38 Ativadas por Mitógeno
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Indóis
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Proteínas de Neoplasias
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Proteínas do Tecido Nervoso
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article